Tableted chewing gum with enhanced delivery of cannabinoids

ABSTRACT

The present invention relates to a tableted chewing gum composition for oral administration of cannabinoids, the composition comprising water-soluble chewing gum ingredients and water-insoluble gum base located in a plurality of particles, wherein the chewing gum composition comprises one or more cannabinoids, and wherein the chewing gum composition generates saliva and delivers more than 20% by weight of the one or more cannabinoids to the oral mucosa during the first 5 minutes of chewing.

FIELD OF THE INVENTION

The invention relates to the field of cannabinoids and alleviation ortreatment of a condition with one or more cannabinoids. In particular,the invention relates to a tableted chewing gum composition providingenhanced delivery of cannabinoids to the oral mucosa.

BACKGROUND OF THE INVENTION

Various attempts have been reported in the prior art with respect todelivery of cannabinoids to patients in need thereof. While cannabinoidsmay be administered and delivered to patients in need thereof throughalveoli in the lungs by smoking, other administration forms providecannabinoids in vapor for lung absorption. Mouth sprays have also beenprovided for medical indications, such as multiple sclerosis.

Only few examples of chewing gum as a vehicle for cannabinoids have beenreported in the prior art. While focus has generally been directed toclinical studies supporting various effects of cannabinoids to the humanbody, only very limited attention is given in the prior art with respectto improvements of chewing gum as a delivery vehicle of cannabinoids.

In particular, one of the critical factors associated with delivery ofcannabinoids from chewing gum is uptake of cannabinoids through the oralmucosa. Chewing gum formulations that may promote a high delivery ofcannabinoids to the oral mucosa without adversely affecting sensoricsproperties may be particularly preferred. If cannabinoids contained inchewing gum are released to the oral saliva without being delivered tothe oral mucosa, the uptake and associated health benefits may be absentor limited to a substantial degree.

Since chewing gum is a complex matrix of various types of componentswhich all interact with each other, providing the chewing gum withspecified properties, it has been a challenge to provide chewing gumplatforms that offer a beneficial delivery of cannabinoids to the oralmucosa. One of the problems is that cannabinoids may be released to theoral saliva without being delivered to the oral mucosa. An associatedproblem is that a slow transfer of cannabinoids from oral saliva to theoral mucosa, caused by an improper chewing gum formulation, may lead toexcessive swallowing of cannabinoids which in effect may cause adverseeffects and limited health benefits.

WO 2009/120080 discloses the use of chewing gum as a medical carrier andrelease vehicle of cannabinoids. The chewing gum disclosed herein mayfacilitate prolonged release of cannabinoids compared to other types ofadministering methods. However, various problems and challenges areassociated with the chewing gum disclosed, partly based on the specificproperties of cannabinoids. While certain specific conventional gumbases are used in formulating the chewing gum disclosed, it appearsunknown if such chewing gum is able to offer a beneficial delivery ofcannabinoids to the oral mucosa.

In general, less attention is addressed in the prior art to the impactof the chewing gum platform and components in the gum base for thedelivery of cannabinoids to the oral mucosa. Also, less attention isgiven on the impact of the chewing gum platform and components in thegum base for the sensorics properties of chewing gum with cannabinoids.Here, important sensorics properties include initial chew, texture,flavor perception, sweetness perception and off-notes associated withcannabinoids. These properties are both relevant from a convenienceperspective in chewing gum, but certainly also in order to support anappropriate delivery of cannabinoids from chewing gum and avoid adverseside effects of cannabinoids.

Hence, there is a need in the prior art for improved chewing gumformulations that solve the above-referenced challenges and problems ofthe prior art. In particular, there is a need in the prior art for newgum base formulations for use in chewing gum that support appropriatedelivery of cannabinoids to the oral mucosa combined with beneficialsensorics properties.

SUMMARY OF THE INVENTION

Accordingly, there is provided a tableted chewing gum composition fororal administration of cannabinoids, the composition comprisingwater-soluble chewing gum ingredients and water-insoluble gum baselocated in a plurality of particles, wherein the chewing gum compositioncomprises one or more cannabinoids, and wherein the chewing gumcomposition generates saliva and delivers more than 20% by weight of theone or more cannabinoids to the oral mucosa during the first 5 minutesof chewing.

The present invention may solve various problems of the prior art andaims at establishing a chewing gum that combines beneficial deliveryproperties of cannabinoids combined with advantageous sensoricsproperties.

One of the aims of the present invention is to provide a chewing gumformulation that offers a high degree of delivery of cannabinoids to theoral mucosa. If cannabinoids contained in chewing gum are released tothe oral saliva without being delivered to the oral mucosa, the uptakeand associated health benefits may be absent or limited to a substantialdegree.

Since chewing gum is a complex matrix of various types of componentswhich all interact with each other, providing the chewing gum withspecified properties, it has been a challenge to provide chewing gumplatforms that offer a beneficial delivery of cannabinoids to the oralmucosa. One of the problems is that cannabinoids may be released to theoral saliva without being delivered to the oral mucosa. An associatedproblem is that a slow transfer of cannabinoids from oral saliva to theoral mucosa, caused by an improper chewing gum formulation, may lead toexcessive swallowing of cannabinoids which in effect may cause adverseeffects and limited health benefits.

Generally, the chewing gum platform applied in the present invention isa particulate chewing gum formulation that is tableted into a coherenttablet. The specific platform of the present invention provides somebeneficial properties compared to chewing gum that is made by rollingand scoring, so-called extruded chewing gum.

Delivery of one or more cannabinoids to the oral mucosa of at least 20%by weight of the one or more cannabinoids to the oral mucosa during thefirst 5 minutes of chewing is considered to be high in the presentcontext. It is required that the chewing gum is formulated to generatesaliva that may help transporting cannabinoids to the oral mucosa.Hence, the tableted chewing gum according to the invention is inherentlyformulated to generate saliva. Saliva may be promoted by the content ofwater-insoluble gum base upon mechanical actions from chewing. Salivamay also be promoted by release of one or more water-soluble chewing gumingredients upon chewing.

Specifically, the provision of a plurality of particles is beneficial interms of delivery of cannabinoids, where a first population of particlesmay comprise water-insoluble gum base and a second population ofparticles may comprise water-soluble chewing gum ingredients, the secondpopulation of particles being free of water-insoluble gum base. Thisspecial construction of delivering cannabinoids provides some benefitsthat are not envisaged in conventional extruded chewing gum.

A very important aspect of the present invention is the provision ofbeneficial sensorics properties. Here, important sensorics propertiesinclude initial chew, texture, flavor perception, sweetness perceptionand off-notes associated with cannabinoids. These properties are bothrelevant from a convenience perspective in chewing gum, but certainlyalso in order to support an appropriate delivery of cannabinoids fromchewing gum.

The present inventors have shown very surprising results with thespecific combination of features of the present invention in terms ofthese sensorics properties. It was an unexpected result that theinvention could both contribute to an improved delivery of cannabinoidsand at the same time provide very beneficial sensorics properties whichin terms may also support an appropriate delivery of cannabinoids fromchewing gum and avoid adverse side effects of cannabinoids.

The taste masking challenge is more profound when a higher release ofcannabinoids are delivered by such chewing gum. If off-notes are thepredominant sensation during administration, convenience may be affectedand even more critically, the delivery of cannabinoids may also beaffected. Saliva production may be suppressed, and the delivery vehiclemay not be handled correctly.

One of the sensorics properties that are particularly advantageous isthe initial chew. Both in order to secure a desired delivery ofcannabinoids and to improve the sensation by a consumer, it is criticalthat the initial chew is improved. Also, the texture of the chewing gumduring chewing is critical for the delivery of cannabinoids and theexperience as well as convenience during chewing. These properties maybe improved by the present invention which was not expected by theinventors of the present invention.

The present gum base may also offer improved taste masking in the sensethat the gap between the delivery of the cannabinoid and the tastemasking ingredients may be overall reduced.

Another important result of the specific combination of cannabinoids andgum base composition is that a reduced content of cannabinoids willreduce the requirements for taste masking, or alternatively make thetaste masking more efficient. This is important given the fact that whenapplied as a medical delivery platform, many patients may havedifficulties in sensing the taste of cannabinoid.

It should also be noted that this unexpected effect is very attractivein relation to medicated chewing gum in the present context as a largegroup of the patients who may benefit from the inventive chewing gumwill be very vulnerable to off-notes.

In an embodiment of the invention, at least 10% by weight of the one ormore cannabinoids are present in unbound form.

A particular advantage is seen when the cannabinoids are present inunbound form. In general, the cannabinoids are present in unbound form.By “unbound form” is meant that the cannabinoids are not bound to anycarrier material that limits free transfer and release of thecannabinoids in the chewing gum formulation. An example of “bound form”is if the cannabinoids are part of a plant material and the cannabinoidsare not extracted and separated from the plant material. Other examplesmay be a pre-blend of microcrystalline cellulose which was seen by theinventors to limit free transfer of cannabinoids in the chewing gumformulation. Also, in some embodiments, other pre-blends withwater-insoluble carrier are to be avoided due to both problems withsensation appearance and release of cannabinoids.

The advantage of having the cannabinoids in free form may also beimproved sensorics characteristics. For instance, plant material maycompromise the chewing gum matrix and for instance microcrystallinecellulose may impact the texture of the chewing gum and the complexmatrix of chewing gum in general.

Within the limits of the present invention, a certain content ofcannabinoids may be present in bound form as long as a certain amountwill also be present in unbound form.

In an embodiment of the invention, at least 90% by weight of the one ormore cannabinoids are present in unbound form.

The advantage of having the cannabinoids in free form may also beimproved sensorics characteristics. For instance, plant material maycompromise the chewing gum matrix and for instance microcrystallinecellulose may impact the texture of the chewing gum and the complexmatrix of chewing gum in general.

In an embodiment of the invention, the chewing gum composition deliversmore than 30% by weight of the one or more cannabinoids to the oralmucosa during the first 5 minutes of chewing.

In an embodiment of the invention, the chewing gum composition deliversat least 40% by weight of the one or more cannabinoids to the oralmucosa during the first 5 minutes of chewing.

In an embodiment of the invention, the chewing gum composition deliversat most 75% by weight of the one or more cannabinoids to the oral mucosaduring the first 5 minutes of chewing.

In certain embodiments of the invention, the delivery may be relativelyhigh. This may for instance be the case when cannabinoids are located indifferent particles, different areas of the tableted chewing gum or bothlocated in the tableted chewing gum and at the same time in an outerhard coating of the tableted chewing gum.

In some embodiments, the present invention may solve various problems ofthe prior art and aims at establishing a chewing gum that combinesbeneficial delivery properties of cannabinoids combined withadvantageous sensorics properties, such as initial chew, texture, flavorperception, sweetness perception and off-notes associated withcannabinoids. These properties are both relevant from a convenienceperspective in chewing gum, but certainly also in order to support anappropriate delivery of cannabinoids and avoid adverse side effects ofcannabinoids.

In an embodiment of the invention, the chewing gum composition deliversmore than 20 and less than 75% by weight of the one or more cannabinoidsto the oral mucosa during the first 5 minutes of chewing.

In certain embodiments of the invention, the delivery may be within therange of more than 20 to less than 75% by weight of the one or morecannabinoids within the first 5 minutes upon oral administration. Adelivery of more than 75% may be critical in some embodiments. In somecircumstances, it is beneficial that the delivery is not too high due toadverse effects, such as off-note problems for a patient under medicaltreatment with cannabinoids.

Still, the cannabinoids may be located in the tableted chewing gumcomposition in locations such as in different particles, different areasof the tableted chewing gum or both located in the tableted chewing gumand at the same time in an outer hard coating of the tableted chewinggum.

In some embodiments, the present invention may solve various problems ofthe prior art and aims at establishing a chewing gum that combinesbeneficial delivery properties of cannabinoids combined withadvantageous sensorics properties, such as initial chew, texture, flavorperception, sweetness perception and off-notes associated withcannabinoids. These properties are both relevant from a convenienceperspective in chewing gum, but certainly also in order to support anappropriate delivery of cannabinoids and avoid adverse side effects ofcannabinoids.

In an embodiment of the invention, the chewing gum composition deliversat most 60% by weight of the one or more cannabinoids to the oral mucosaduring the first 5 minutes of chewing.

In some circumstances, it is beneficial that the delivery rate is nottoo high due to adverse effects, such as off-note problems for a patientunder medical treatment with cannabinoids. Still, the cannabinoids maybe located in the tableted chewing gum composition in locations such asin different particles, different areas of the tableted chewing gum orboth located in the tableted chewing gum and at the same time in anouter hard coating of the tableted chewing gum.

In an embodiment of the invention, the chewing gum composition deliversmore than 20 and less than 60% by weight of the one or more cannabinoidsto the oral mucosa during the first 5 minutes of chewing.

In certain embodiments of the invention, a preferred delivery may bewithin the range of more than 20 and less than 60% by weight of the oneor more cannabinoids within the first 5 minutes upon oraladministration. A delivery of more than 20% is considered to be at anadvantageous level.

In an embodiment of the invention, the amount of the one or morecannabinoids is at least 5 mg.

In an embodiment of the invention, the amount of the one or morecannabinoids is at least 10 mg.

In an embodiment of the invention, delivery of the one or morecannabinoids is measured when chewing 60 chews each minute.

In an embodiment of the invention, delivery of the one or morecannabinoids is measured when saliva is not swallowed during the 5minutes of chewing.

In an embodiment of the invention, delivery of the one or morecannabinoids is measured when saliva is collected during and after the 5minutes of chewing and analyzed for content of the one or morecannabinoids.

In an embodiment of the invention, delivery of the one or morecannabinoids is measured when chewing 60 chews each minute and saliva isnot swallowed during the 5 minutes of chewing.

In an embodiment of the invention, delivery of the one or morecannabinoids is measured when chewing 60 chews each minute and whensaliva is collected during and after the 5 minutes of chewing andanalyzed for content of the one or more cannabinoids.

In an embodiment of the invention, delivery of the one or morecannabinoids is measured when saliva is not swallowed during the 5minutes of chewing and when saliva is collected during and after the 5minutes of chewing and analyzed for content of the one or morecannabinoids.

In an embodiment of the invention, delivery of the one or morecannabinoids is measured when chewing 60 chews each minute and whensaliva is not swallowed during the 5 minutes of chewing and when salivais collected during and after the 5 minutes of chewing and analyzed forcontent of the one or more cannabinoids.

In an embodiment of the invention, delivery of the one or morecannabinoids is partly controlled by means of the composition of thewater-insoluble gum base.

One of the aims of the present invention is to provide a chewing gumformulation that both offers a relatively high delivery of cannabinoidsand at the same time possesses beneficial or superior sensoricsproperties. Furthermore, it is contemplated that the present inventionmay be directed to improvements of the chewing gum vehicle for thepurpose of improving delivery of cannabinoids without addition ofcomponents that may interact with sensorics properties of the gum.

In an embodiment of the invention, the gum base is comprising one ormore natural resins in an amount of 10-40% by weight of the gum base.

In an embodiment of the invention, delivery of the one or morecannabinoids is partly controlled by means of the amount of the one ormore natural resins.

The natural resins provide beneficial properties to the presentinvention. In particular the combination of natural resins and elastomerplasticizers provides beneficial properties to the gum base andfollowingly to the chewing gum formulation in general, both in terms ofdelivery properties of cannabinoids and sensorics properties.

In an embodiment of the invention, the gum base comprising one or moreelastomers in an amount of 3-30% by weight of the gum base, and one ormore elastomer plasticizers in an amount of 8-50% by weight of the gumbase.

The elastomer plasticizers provide beneficial properties to the presentinvention. In particular the combination of natural resins and elastomerplasticizers provides beneficial properties to the gum base andfollowingly to the chewing gum formulation in general, both in terms ofdelivery properties of cannabinoids and sensorics properties.

In an embodiment of the invention, delivery of the one or morecannabinoids is partly controlled by means of the amount of the one ormore elastomer plasticizers.

The provision of one or more elastomer plasticizers is particularlyadvantageous for the delivery characteristics of cannabinoids. It wasunexpected to the present inventors that the combination of the specificchewing gum platform according to the invention with the one or moreelastomer plasticizers would contribute to improved deliverycharacteristics of cannabinoids.

Importantly, the elastomer plasticizer in the present context serves toplasticize the elastomers present in the gum base. The elastomerplasticizers are not to be considered elastomers by themselves in thepresent context. The elastomeric properties are provided by theelastomers of the invention, and the elastomer plasticizers are presentto plasticize the elastomers in order to obtain the beneficial deliverycharacteristics of the present invention.

The special combination of gum base components of the present inventionwith one or more natural resins in a certain amount combined with one ormore elastomer plasticizers in a certain amount is particularlyadvantageous for delivery characteristics of cannabinoids. It wasunexpected to the present inventors that the combination according tothe invention would contribute to improved delivery characteristics ofcannabinoids. Importantly, the elastomer plasticizer in the presentcontext serves to plasticize the elastomers present in the gum base. Theelastomer plasticizers are not to be considered elastomers by themselvesin the present context. The elastomeric properties are provided by theelastomers of the invention, and the elastomer plasticizers are presentto plasticize the elastomers in order to obtain the beneficial deliverycharacteristics of the present invention.

In an embodiment of the invention, the gum base comprising one or morepolyvinyl acetate elastomer plasticizers in an amount of 8-50% by weightof the gum base.

Traditionally, water-insoluble gum base is seen as a matrix that doesnot offer a high degree of delivery of cannabinoids. In particular, withrespect to cannabinoids, it is a surprise that improved delivery may beseen when polyvinyl acetate elastomer plasticizers are applied in thegum base.

In an embodiment of the invention, the one or more polyvinyl acetateelastomer plasticizers are present in an amount of 15-35% by weight ofthe gum base.

A particularly preferred range of polyvinyl acetate elastomerplasticizers is 15-35% by weight of the gum base. Here, veryadvantageous results were achieved with respect to delivery ofcannabinoids and sensorics characteristics, such as initial chew,texture, flavor perception, sweetness and off-notes. That the preferredrange would be on a level such high was a surprise to the inventors.Also, it was not expected that such high amount of polyvinyl acetateelastomer plasticizers would have a combined effect of improvedsensorics properties.

In other embodiments of the invention, the one or more polyvinyl acetateelastomer plasticizers are present in an amount of 17-33% by weight ofthe gum base. In other embodiments of the invention, the one or morepolyvinyl acetate elastomer plasticizers are present in an amount of20-35% by weight of the gum base. In other embodiments of the invention,the one or more polyvinyl acetate elastomer plasticizers are present inan amount of 20-30% by weight of the gum base. In other embodiments ofthe invention, the one or more polyvinyl acetate elastomer plasticizersare present in an amount of 15-40% by weight of the gum base. In otherembodiments of the invention, the one or more polyvinyl acetateelastomer plasticizers are present in an amount of 20-40% by weight ofthe gum base.

In an embodiment of the invention, the water-insoluble gum base is anatural gum base comprising natural ingredients, such as chicle.

In an embodiment of the invention, delivery of the one or morecannabinoids is partly controlled by means of the water-soluble chewinggum ingredients.

The water-soluble ingredients provide beneficial properties to thepresent invention. In particular, when water-soluble chewing gumingredients are combined with natural resins and elastomer plasticizersof the present invention, beneficial properties to the gum base applies,both in terms of delivery properties of cannabinoids and sensoricsproperties.

In an embodiment of the invention, the plurality of particles includinga first population of particles comprising water-insoluble gum base anda second population of particles comprising water-soluble chewing gumingredients.

Specifically, the provision of at least two populations of particles isbeneficial in terms of delivery of cannabinoids, where a firstpopulation of particles comprises water-insoluble gum base and a secondpopulation of particles comprises water-soluble chewing gum ingredients,the second population of particles being free of water-insoluble gumbase. This special construction of delivering cannabinoids provides somebenefits that are not envisaged in conventional extruded chewing gum.

In an embodiment of the invention, the first population of particles ispresent in an amount of at least 15% by weight of the tableted chewinggum composition.

Generally, since the first population of particles comprise gum base,the amount of these types of particles impact the content of gum base inthe tableted chewing gum. For instance, when the content of gum base isabout 100% by weight of the first population of particles, the gum basecontent of the tableted chewing gum may be as low as 15% by weight ofthe tableted chewing gum composition. On the other hand, when thecontent of gum base is about 40% by weight of the first population ofparticles, the gum base content of the tableted chewing gum may also beas low as 15% by weight of the tableted chewing gum composition. In thiscase, the amount of the first population of particles is higher than 15%by weight of the tableted chewing gum composition.

In an embodiment of the invention, wherein the first population ofparticles is present in an amount of 15 to 95% by weight of the tabletedchewing gum composition.

Typically, the gum base content of the tableted chewing gum compositionis higher than 15% by weight of the tableted chewing gum composition,such as about 40% by weight of the tableted chewing gum composition. Inthis case, the amount of the first population of particles may be 40% byweight of the tableted chewing gum composition when the gum base contentin the first population of particles is about 100% by weight of thefirst population of particles. In another case, the amount of the firstpopulation of particles may be 80% by weight of the tableted chewing gumcomposition when the gum base content in the first population ofparticles is about 50% by weight of the first population of particles.This gives an amount of gum base of the tableted chewing gum compositionof about 40% by weight of the tableted chewing gum composition.

In an embodiment of the invention, the first population of particles ispresent in an amount of 15 to 90% by weight of the tableted chewing gumcomposition. In an embodiment of the invention, the first population ofparticles is present in an amount of 20 to 95% by weight of the tabletedchewing gum composition. In an embodiment of the invention, the firstpopulation of particles is present in an amount of 20 to 90% by weightof the tableted chewing gum composition. In an embodiment of theinvention, the first population of particles is present in an amount of20 to 80% by weight of the tableted chewing gum composition.

In an embodiment of the invention, the first population of particles ispresent in an amount of at least 20% by weight of the tableted chewinggum composition.

Preferably, the gum base content of the tableted chewing gum compositionis about 40% by weight of the tableted chewing gum composition. In someembodiments of the invention, the amount of the first population ofparticles may be 40% by weight of the tableted chewing gum compositionand the gum base content in the first population of particles is about100% by weight of the first population of particles.

In some other embodiments of the invention, the amount of the firstpopulation of particles may be about 90% by weight of the tabletedchewing gum composition and the gum base content in the first populationof particles is about 40% by weight of the first population ofparticles. This gives an amount of gum base of the tableted chewing gumcomposition of about 36% by weight of the tableted chewing gumcomposition. In this case, the first population of particles may be thedominant particles of the composition, preferably containing a majorityof the water-soluble ingredients of the present invention. In someembodiments of the invention, the second population of particles mainlycontains flavors and auxiliary ingredients, while the water-solublechewing gum ingredients are primarily contained in the first populationof particles together with gum base.

In an embodiment of the invention, the first population of particles ispresent in an amount of at least 30% by weight of the tableted chewinggum composition. In an embodiment of the invention, the first populationof particles is present in an amount of at least 40% by weight of thetableted chewing gum composition. In an embodiment of the invention, thefirst population of particles is present in an amount of at least 50% byweight of the tableted chewing gum composition. In an embodiment of theinvention, the first population of particles is present in an amount ofat least 70% by weight of the tableted chewing gum composition. In anembodiment of the invention, the first population of particles ispresent in an amount of at least 90% by weight of the tableted chewinggum composition.

In an embodiment of the invention, the first population of particles ispresent in an amount of 20 to 60% by weight of the tableted chewing gumcomposition.

While a preferred amount of gum base in the tableted chewing gumcomposition is about 40% by weight of the tableted chewing gumcomposition, the amount of gum base may be varied according to theinvention.

In an embodiment of the invention, the first population of particles ispresent in an amount of 30 to 60% by weight of the tableted chewing gumcomposition. In an embodiment of the invention, the first population ofparticles is present in an amount of 30 to 50% by weight of the tabletedchewing gum composition.

In an embodiment of the invention, the second population of particles ispresent in an amount of at least 40% by weight of the tableted chewinggum composition.

While the first population of particles contains gum base, the secondpopulation of particles does not contain gum base. The second populationof particles may essentially consist of water-soluble ingredients, whichis presently preferred. However, the second population of particles mayalso contain water-insoluble ingredients, such as talc, cellulose, orother water-insoluble tableting material.

In some other embodiments of the invention, the amount of the secondpopulation of particles may be about 60% by weight of the tabletedchewing gum composition and the content of water-soluble ingredients inthe second population of particles may be about 100% by weight of thesecond population of particles. This gives an amount of water-solubleingredients of the tableted chewing gum composition of about 60% byweight of the tableted chewing gum composition. In this case, the secondpopulation of particles may be the dominant particles of thecomposition, preferably containing a majority of the water-solubleingredients of the present invention.

In an embodiment of the invention, the second population of particles ispresent in an amount of 40 to 80% by weight of the tableted chewing gumcomposition. In an embodiment of the invention, the second population ofparticles is present in an amount of 40 to 70% by weight of the tabletedchewing gum composition. In an embodiment of the invention, the secondpopulation of particles is present in an amount of 50 to 80% by weightof the tableted chewing gum composition. In an embodiment of theinvention, the second population of particles is present in an amount of50 to 70% by weight of the tableted chewing gum composition.

In an embodiment of the invention, the content of water-insoluble gumbase of the first population of particles is more than 30% by weight ofthe first population of particles. In an embodiment of the invention,the content of water-insoluble gum base of the first population ofparticles is more than 40% by weight of the first population ofparticles. In an embodiment of the invention, the content ofwater-insoluble gum base of the first population of particles is morethan 50% by weight of the first population of particles. In anembodiment of the invention, the content of water-insoluble gum base ofthe first population of particles is more than 70% by weight of thefirst population of particles.

In an embodiment of the invention, the content of water-insoluble gumbase of the first population of particles is more than 90% by weight ofthe first population of particles, such as about 100% by weight of thefirst population of particles.

In an embodiment of the invention, the content of water-soluble chewinggum ingredients of the second population of particles is more than 50%by weight of the second population of particles, the second populationof particles being free of water-insoluble gum base.

Preferably, the water-soluble chewing gum ingredients comprise one ormore sugar alcohols. In the alternative, the water-soluble chewing gumingredients comprise one or more sugars.

In an embodiment of the invention, the content of water-soluble chewinggum ingredients of the second population of particles is more than 60%by weight of the second population of particles.

In an embodiment of the invention, the content of water-soluble chewinggum ingredients of the second population of particles is more than 70%by weight of the second population of particles.

In an embodiment of the invention, the content of water-soluble chewinggum ingredients of the second population of particles is more than 90%by weight of the second population of particles, the second populationof particles being free of water-insoluble gum base.

In an embodiment of the invention, the first population of particles isreduced in volume and cohered together resulting in a matrix of discreteareas of the tablet.

According to the invention, tableting implies that the population ofparticles is reduced in volume as a result of pressure applied in thetableting apparatus. Hence, while the population of particles may befree-flowing before tableting, once the particles have been pressed aspart of a population of particles, and optionally additional populationof particles, the volume of the particles is reduced, and the particlesare cohered together into a continuous matrix, which in the presentcontext is denoted a ‘layer’.

In the present context, it is to be understood that the individualparticles are not merged after tableting but remain individual‘discrete’ areas after tableting, constituting the individual particles.For instance, if a particle of the first population of particles has asize of about 1 mm, the size of such a particle may be 0.9 mm aftertableting and have an appearance of a discrete area cohered togetherrandomly with particles at the outer borders of the particle, includingparticles of the second population of particles. Some integration of theparticles may be present but generally the particles remains discreteareas of the tablet.

In an embodiment of the invention, the second population of particles isreduced in volume and cohered together resulting in a matrix of discreteareas of the tablet.

In the present context, it is to be understood that the individualparticles are not merged after tableting but remain individual‘discrete’ areas after tableting, constituting the individual particles.For instance, if a particle of the second population of particles has asize of about 0.1 mm, the size of such a particle may be 0.09 mm aftertableting and have an appearance of a discrete area cohered togetherrandomly with particles at the outer borders of the particle, includingparticles of the first population of particles.

In an embodiment of the invention, the first population of particles andthe second population of particles are reduced in volume and coheredtogether resulting in a matrix of discrete areas of the tablet.

In an embodiment of the invention, the first population of particles andthe second population of particles are substantially homogeneouslydistributed in the tableted chewing gum composition.

Preferably, the first population of particles and the second populationof particles are homogeneously distributed in the tableted chewing gumcomposition. This may be secured by using adequate mixing containers andavoid segregation of particles before applying the particles to thetableting apparatus. Due to potential size difference between the firstpopulation of particles and the second population of particles, the twotypes of particles may be mixed in a mixing container immediately beforetableting is applied.

In an embodiment of the invention, the plurality of particles compriseone or more further population of particles.

While it is preferred that two populations of particles are applied, oneor more further population of particles may be applied in the presentinvention. For instance, a population of particles consisting ofwater-insoluble tableting aids, such as talc, may be applied accordingto the invention. In other embodiments, one or more additionalpopulation of particles containing water-soluble ingredients may beapplied as well as one or more further populations of particles with acontent of gum base. The aim of the annotation ‘first population ofparticles’ and ‘second population of particles’ is to make a distinctionbetween particles that contain gum base and particles that do notcontain gum base.

In an embodiment of the invention, the tableted chewing gum compositioncomprises one or more further population of particles.

In an embodiment of the invention, the one or more cannabinoids arepresent in the first population of particles comprising water-insolublegum base.

In an embodiment of the invention, the one or more cannabinoids arepresent in the second population of particles comprising water-solublechewing gum ingredients.

In an embodiment of the invention, the first population of particles andthe second population of particles are substantially homogeneouslydistributed in a first layer of the tableted chewing gum composition.

In the present context, a ‘layer’ is to be understood as a matrixresulting from pressing one portion of particles according to theinvention. Hence, if only one portion of particles according to theinvention is applied in the tableting apparatus, and this portion ispressed into a coherent tablet, this would correspond to one ‘layer’ ora ‘first layer’. This portion may comprise one or more populations ofparticles. Optionally, such layer may be pressed in two steps withvarying pressure. On the other hand, if another portion of particlesaccording to the invention is applied to the tableting apparatus on topof the already pressed layer, this would correspond to another ‘layer’or a ‘second layer’. In the context of the invention, the second layermay also be applied in the tableting apparatus first and the first layermay be applied in the tableting apparatus in a second step.

Due to the inherent nature of conventional tablet pressing, theindividual layers of a tableted composition would have a sharp linebetween the layers when the layers are pressed in two or more subsequentsteps. This is seen from a side view of the tablet as distinct layers ontop of each other. In an alternative embodiment, two or more portionsare applied in subsequent steps to the tableting apparatus and pressedin one sequence. In this case there will not be a sharp line between thelayers from a side view, but this would still be considered a layeredtablet according to the invention, although the line between the layerswould be irregular. Accordingly, in some embodiments, it is not requiredthat layers are processed in separate tableting steps.

In an embodiment of the invention, the water-insoluble gum base ispartly located in a first layer of the chewing gum composition and thewater-soluble chewing gum ingredients are partly located in a secondlayer of the chewing gum composition.

Preferably, when a multi-layered tableted chewing gum composition isapplied, it may be beneficial to partly locate the water-insoluble gumbase in one layer and a part of the water-soluble chewing gumingredients in another layer. This may both influence the delivery ofthe one or more cannabinoids of the composition as well as the sensoricsproperties of the tableted chewing gum composition.

In an embodiment of the invention, the water-insoluble gum base ispartly located in a first layer of the chewing gum composition and thewater-soluble chewing gum ingredients are partly located in a secondlayer of the chewing gum composition together with the one or morecannabinoids.

In an embodiment of the invention, the water-insoluble gum base islocated in a first layer of the chewing gum composition and thewater-soluble chewing gum ingredients are partly located in a secondlayer of the chewing gum composition.

In one embodiment, when a multi-layered tableted chewing gum compositionis applied, it may be beneficial to only locate the water-insoluble gumbase in one layer, and a part of the water-soluble chewing gumingredients in another layer or layers. This may both influence thedelivery of the one or more cannabinoids of the composition as well asthe sensorics properties of the tableted chewing gum composition.

In an embodiment of the invention, the water-insoluble gum base islocated in a first layer of the chewing gum composition and thewater-soluble chewing gum ingredients are partly located in a secondlayer of the chewing gum composition together with the one or morecannabinoids.

In an embodiment of the invention, the water-insoluble gum base ispartly located in a first layer of the chewing gum composition andpartly in a second layer of the chewing gum composition.

In certain embodiments of the invention, a two-layered tableted chewinggum composition is provided with two layers comprising gum base. Thisconfiguration may be beneficial with respect to the delivery of the oneor more cannabinoids of the composition as well as the sensoricsproperties of the tableted chewing gum composition.

In an embodiment of the invention, the water-soluble chewing gumingredients are partly located in a first layer of the chewing gumcomposition and partly in a second layer of the chewing gum composition.

In an embodiment of the invention, the content of water-insoluble gumbase of the first layer is more than 30% by weight of the first layer.

In an embodiment of the invention, the content of water-insoluble gumbase of the first layer is more than 35% by weight of the first layer.In an embodiment of the invention, the content of water-insoluble gumbase of the first layer is more than 40% by weight of the first layer.

In an embodiment of the invention, the content of water-insoluble gumbase of the first layer is more than 90% by weight of the first layer.

In an embodiment of the invention, the content of water-insoluble gumbase of the first layer is from 30 to 90% by weight of the first layer.In an embodiment of the invention, the content of water-insoluble gumbase of the first layer is from 30 to 70% by weight of the first layer.In an embodiment of the invention, the content of water-insoluble gumbase of the first layer is from 30 to 60% by weight of the first layer.In an embodiment of the invention, the content of water-insoluble gumbase of the first layer is from 35 to 70% by weight of the first layer.In an embodiment of the invention, the content of water-insoluble gumbase of the first layer is from 35 to 60% by weight of the first layer.In an embodiment of the invention, the content of water-insoluble gumbase of the first layer is from 30 to 50% by weight of the first layer

In an embodiment of the invention, the content of water-soluble chewinggum ingredients of the second layer is more than 50% by weight of thesecond layer

In an embodiment of the invention, the content of water-soluble chewinggum ingredients of the second layer is more than 90% by weight of thesecond layer.

In an embodiment of the invention, the content of water-soluble chewinggum ingredients of the second layer is about 100% by weight of thesecond layer.

In an embodiment of the invention, the tableted chewing gum compositionconsists of two layers where a first layer is cohered to and adjacent toa second layer.

In the present context ‘cohered to and adjacent to’ is intended to meanthat two layers are pressed together on one top side and one bottom sideof two portions of particles comprising one or more populations ofparticles. Hence, one surface of a layer is attached to one surface ofanother layer, whereas additional surfaces of the portions are notexposed to each other. Seen from a side view, the layers have atablet-slice appearance.

In an embodiment of the invention, the tableted chewing gum compositionconsists of three layers where one middle layer is cohered to andadjacent to two outer layers.

In the present context ‘cohered to and adjacent to’ is intended to meanthat two outer layers are located on and attached to one top side andone bottom side of a middle layer. Seen from a side view, the layershave a tablet-slice appearance.

In an embodiment of the invention, the water-soluble chewing gumingredients comprise one or more sugar alcohols or one or more sugars inan amount of 35-80% by weight of the tableted chewing gum composition.

In an embodiment of the invention, the water-soluble chewing gumingredients comprise one or more sugar alcohols or one or more sugars inan amount of 40-70% by weight of the tableted chewing gum composition.

It is particularly preferred that the water-soluble chewing gumingredients are present in an amount of 40-70% by weight of the chewinggum. This range of water-soluble chewing gum ingredients have shownparticularly beneficial results. The inventors of the present inventiondid not expect that an improved delivery would be possible within thisrange of water-soluble chewing gum ingredients. As the water-solublechewing gum ingredients are mixed into the gum base during themanufacturing process, it was expected the water-soluble ingredients didnot provide enough porosity of the chewing gum to facilitate an improveddelivery. In addition, due to the specific properties of cannabinoids,it was a surprise to discover that the delivery of cannabinoids wasimproved with water-soluble chewing gum ingredients.

Importantly, the sensorics characteristics were thought to becompromised when the water-soluble chewing gum ingredients are presentin an amount of 40-70% by weight of the chewing gum. However, contraryto expectations, the sensorics properties were improved in combinationwith an improved delivery of cannabinoids. In particular, the texture ofthe chewing gum was improved. It was expected that the texture would beworse with this amount of water-soluble ingredients in the chewing gum.

In an embodiment of the invention, the water-soluble chewing gumingredients comprise one or more sugar alcohols partly located in afirst layer of the chewing gum composition and partly in a second layerof the chewing gum composition, and wherein the same type of sugaralcohols is present in both layers.

In an embodiment of the invention, the water-soluble chewing gumingredients comprise one or more sugar alcohols partly located in afirst layer of the chewing gum composition and partly in a second layerof the chewing gum composition, and wherein different types of sugaralcohols are present in the layers.

In an embodiment of the invention, the one or more cannabinoids are partof the water-soluble chewing gum ingredients.

In an embodiment of the invention, delivery of the one or morecannabinoids is partly controlled by means of the location of the one ormore cannabinoids in the chewing gum composition.

In an embodiment of the invention, the one or more cannabinoids arelocated in a first layer of the chewing gum composition.

In an embodiment of the invention, the one or more cannabinoids arelocated in a second layer of the chewing gum composition.

In an embodiment of the invention, the one or more cannabinoids are bothcomprised in a first layer of the chewing gum composition and in asecond layer of the chewing gum composition.

In an embodiment of the invention, delivery of the one or morecannabinoids is partly controlled by means of further release enhancingingredients.

In an embodiment of the invention, the gum base comprises less than 50%by weight of gum base polymers.

In order to achieve the effects of the invention, it may in someembodiments be preferred that the content of polymers is relatively low.This ensures for instance that the delivery of cannabinoids may beimproved and that the sensorics properties of the chewing gum may beimproved. In particular, when vinyl laurate-vinyl acetate copolymers areapplied, it appears critical that the content of gum base polymersshould be below 50% by weight of the gum base polymers. It appears thatthis polymer may compromise the chewing gum formulation in the presentcontext.

In an embodiment of the invention, the gum base does not comprise vinyllaurate-vinyl acetate copolymer.

To the surprise of the inventors, it was seen that vinyl laurate-vinylacetate copolymer may compromise the release of cannabinoids and thesensorics characteristics of the chewing gum.

Hence, it is preferred that this copolymer is not present in the gumbase.

In certain other embodiments, the gum base polymers comprise less than20% by weight of vinyl laurate-vinyl acetate copolymer. In certain otherembodiments, the gum base polymers comprise less than 15% by weight ofvinyl laurate-vinyl acetate copolymer. In certain other embodiments, thegum base polymers comprise less than 10% by weight of vinyllaurate-vinyl acetate copolymer. In certain other embodiments, the gumbase polymers comprise less than 5% by weight of vinyl laurate-vinylacetate copolymer.

In some embodiments of the invention, if polyvinyl acetate elastomersare present in the gum base formulation, the gum base polymers compriseless than 20% by weight of vinyl laurate-vinyl acetate copolymer, suchas less than 10%, such as less than 5%. In the present context,polyvinyl acetate elastomers are not the same as polyvinyl acetateelastomer plasticizers. Basically, polyvinyl acetate elastomers provideselastomeric properties to the chewing gum, whereas polyvinyl acetateelastomer plasticizers work to plasticize the elastomers present in thegum base.

In an embodiment of the invention, the gum base comprising one or morenatural resins selected from the group consisting of polyterpene resins,resins based on gum rosin, wood rosin or tall oil resin.

In an embodiment of the invention, the gum base comprising one or moreelastomers selected from the group consisting of styrene-butadienecopolymers, polyisobutylene, isobutylene-isoprene copolymers,polyethylene, polyurethane or any combination thereof.

In an embodiment of the invention, the one or more elastomers arepresent in an amount of 3-20% by weight, such as in an amount of 3-15%by weight, such as in an amount of 5-10% by weight.

In an embodiment of the invention, the amount of gum base in the chewinggum composition is 15-60% by weight of the tableted chewing gumcomposition.

In an embodiment of the invention, the chewing gum composition comprisesa pH regulating agent in an amount of at least 0.5% by weight of thechewing gum composition.

In an embodiment of the invention, the release rate of the one or morecannabinoids is more than 20% by weight of the one or more cannabinoidswithin the first 5 minutes upon oral administration.

One of the aims of the present invention is to provide a chewing gumformulation that both offers a relatively rapid release of cannabinoidsand at the same time possesses beneficial or superior sensoricsproperties. Furthermore, it is contemplated that the present inventionmay be directed to improvements of the chewing gum vehicle for thepurpose of improving release of cannabinoids without addition ofcomponents that may interact with sensorics properties of the gum.

With respect to release properties, the present invention may offer animproved release profile of cannabinoids compared to conventional gumbase. In particular, the specific gum base formulation of the presentinvention may serve to provide improved release characteristics ofcannabinoids compared to conventional gum base applied in combinationwith cannabinoids.

In the present context, an improved release profile may refer to ahigher release of cannabinoids which is particularly seen as anadvantage since it has traditionally been a challenge with release ofcannabinoids from chewing gum. In order to obtain beneficial healtheffects both in terms of systemic delivery of cannabinoids as well aslocal delivery of cannabinoids, it is required that a certain content ofcannabinoids is released over time. Hence, rapid release of cannabinoidsmay be an advantage of the present invention.

In addition, the present invention may serve to provide controlledrelease of cannabinoids such that the chewing gum is tailored to deliveran effective content of cannabinoids over time and at the same timeavoid adverse effects of cannabinoids, such as off-notes. Accordingly,the chewing gum of the present invention may at the same time offer arelatively sustained release of cannabinoids.

In an embodiment of the invention, the release rate of the one or morecannabinoids is at least 30% by weight of the one or more cannabinoidswithin the first 5 minutes upon oral administration.

In certain embodiments of the invention, the release rate is preferablyabove 30% within the first 5 minutes after chewing is initiated.

A release rate of more than 30% is considered a relatively rapid, whileat the same time maintaining beneficial sensorics properties.

In some embodiments, the present invention may solve various problems ofthe prior art and aims at establishing a chewing gum that combinesbeneficial delivery properties of cannabinoids combined withadvantageous sensorics properties, such as initial chew, texture, flavorperception, sweetness perception and off-notes associated withcannabinoids. These properties are both relevant from a convenienceperspective in chewing gum, but certainly also in order to support anappropriate delivery of cannabinoids from chewing gum and avoid adverseside effects of cannabinoids.

In an embodiment of the invention, the one or more cannabinoids are notpart of a pre-mixture with microcrystalline cellulose.

In the present context, a premixture is mainly used to allocate the oneor more cannabinoids properly to the manufacturing process and securethat the uniformity is not compromised and that the cannabinoids aredistributed properly into the mixture. Preferably, the cannabinoids areprovided in a premixture with one or more sugar alcohols. It was asurprise to the inventors that a premixture was important to have thecannabinoids distributed properly in the manufacturing process and toend up with a product where the uniformity was consistent.

In an embodiment of the invention, the one or more cannabinoids arepresent in an amount of 0.1 to 200 mg. In some other embodiments of theinvention, the one or more cannabinoids are present in an amount of 0.1to 100 mg. In some other embodiments of the invention, the one or morecannabinoids are present in an amount of 0.1 to 50 mg. In an embodimentof the invention said chewing gum comprises said cannabinoids in anamount of 0.1-30 mg, such as 1-20 mg, such as 5-15 mg.

In an embodiment of the invention, the one or more cannabinoids comprisecannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV),salts and derivatives thereof. In an embodiment of the invention the oneor more cannabinoids comprises CBD, salts and derivatives thereof,including analogues and homologues. In an embodiment of the inventionsaid one or more cannabinoids comprises CBD. In an embodiment of theinvention said one or more cannabinoids is CBD.

In an embodiment of the invention, the one or more cannabinoids comprisetetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA),tetrahydrocannabivarin (THCV), salts and derivatives thereof. In anembodiment of the invention said one or more cannabinoids comprisestetrahydrocannabinol (THC). Preferably THC is intended to mean(−)-trans-Δ⁹-tetrahydrocannabinol, i.e.(6aR,10aR)-delta-9-tetrahydrocannabinol). In an embodiment of theinvention said one or more cannabinoids is THC.

In an embodiment of the invention, the one or more cannabinoids comprisecannabigerol (CBG), salts and derivatives thereof.

In an embodiment of the invention, the one or more cannabinoids compriseat least two cannabinoids. In an embodiment of the invention said one ormore cannabinoids comprises a combination of several cannabinoids, suchas THC and CBD. In an embodiment of the invention said one or morecannabinoids is a combination of THC and CBD.

In an embodiment of the invention the chewing gum comprises gum base inan amount of 30-75% by weight of the chewing gum before any optionallyapplied coating, such as 35-70% by weight of the chewing gum or 40-65%by weight of the chewing gum or 45-60% by weight of the chewing gum.

In an embodiment of the invention the chewing gum comprises wax. In anembodiment of the invention the chewing gum comprises fat.

In an embodiment of the invention the chewing gum comprises flavor in anamount between 0.01 and 10% by weight of the chewing gum such as in anamount between 0.01 and 5% by weight of the chewing gum.

According to an advantageous embodiment of the invention, the chewinggum may be formulated with flavors, e.g. flavors including acids, whichmay be more acceptable for seriously ill patients, such as patientsreceiving chemotherapy.

In an embodiment of the invention the chewing gum comprises highintensity sweetener.

In an embodiment of the invention, the one or more cannabinoids arepresent in solid form. In an embodiment of the invention, the one ormore cannabinoids are present in liquid or semi-liquid form. In anembodiment of the invention, the one or more cannabinoids are present ingranules.

In an embodiment of the invention, the one or more cannabinoids arepresent in a pre-mixture with one or more sugar alcohols or one or moresugars.

In the present context, a pre-mixture is mainly used to allocate the oneor more cannabinoids properly to the manufacturing process and securethat the uniformity is not compromised and that the cannabinoids aredistributed properly into the mixture. Preferably, the cannabinoids areprovided in a premixture with one or more sugar alcohols. It was asurprise to the inventors that a premixture was important to have thecannabinoids distributed properly in the manufacturing process and toend up with a product where the uniformity was consistent.

In an embodiment of the invention, the one or more cannabinoids formpart of a complex with cyclodextrin. This complex may enhance thedelivery of cannabinoids according to the present invention.

In an embodiment of the invention, the one or more cannabinoids compriseat least one phytocannabinoid that forms part of an extract. In someembodiments of the invention, it was seen that cannabinoids as part ofan extract may enhance the delivery of cannabinoids. It was also seenthat the lower concentration applied in the extract, the higherdelivery.

In an embodiment of the invention, the chewing gum further comprisingterpenes, such as at least one terpene that forms part of an extract.

In an embodiment of the invention, the one or more cannabinoids compriseat least one isolated cannabinoid.

In an embodiment of the invention, the one or more cannabinoids compriseat least one water-soluble cannabinoid. Water-soluble cannabinoids mayenhance the delivery according to the present invention.

In an embodiment of the invention, the chewing gum comprises one or moreemulsifiers.

In an embodiment of the invention the chewing gum comprises emulsifiersin an amount of 0.1% to 25% by weight of said chewing gum, such as 1-10%by weight of said chewing gum, such as 2-8% by weight of said chewinggum.

In an embodiment of the invention the emulsifiers are selected from thegroup of acetylated monoglycerides, mono- and/or di-glycerides of fattyacids such as glycerol monostearate, acetem, lecithin and anycombination thereof.

In an embodiment of the invention, the chewing gum comprises one or moresolubilizers.

In an embodiment of the invention, the chewing gum comprises aself-emulsifying agent.

In an embodiment of the invention, the chewing gum comprises a polymercarrier for the one or more cannabinoids.

In an embodiment of the invention, the chewing gum comprises a lipidcarrier for the one or more cannabinoids.

In an embodiment of the invention, the chewing gum comprises enzymeinhibitors.

In an embodiment of the invention, the chewing gum comprises one or moreantioxidants.

In an embodiment of the invention, the one or more cannabinoids have asystemic effect.

In an embodiment of the invention, the one or more cannabinoids have alocal effect.

In an embodiment of the invention, the one or more cannabinoids arecomprised in an outer coating of the chewing gum.

In certain embodiments of the invention, the cannabinoids are present inthe coating of the chewing gum. This is particularly preferred when anenhanced delivery of cannabinoids are preferred. Also, if controlleddelivery of cannabinoids is preferred, it is an advantage to partlyallocate cannabinoids in the coating. It was not expected by theinventors of the present invention that it was possible to use a coatingto deliver cannabinoids. By combining cannabinoids in the coating and inthe chewing gum, controlled delivery of cannabinoids may be provided. Inthe present context, cannabinoids may both be allocated in the coating,in the chewing gum or in both places.

In an embodiment of the invention, the tableted chewing gum compositioncomprises one or more modules that do not comprise particles.

In the present context, a ‘module’ is to be understood as a matrix ofnon-particulate matter, cohered together with the tableted particles ofthe present invention. A ‘module’ may for instance be a sheet ofconventional extruded chewing gum that is applied during the tabletingprocess, such as after a first pressing step in the tableting apparatuswhere the sheet is applied and optionally pressed on top of the alreadypressed tablet. In other embodiments, the extruded sheet may be appliedin other configurations with the tableted particles of the invention.

Another option is to apply a non-particulate capsule, such as a gelcapsule, and pressing this capsule together with the particles of theinvention. This may be done by pressing a first portion of particles andsubsequently locate the gel capsule centrally in a cavity of the pressedmaterial after which another portion of particles is pressed on top ofthe capsule, fully enclosing the capsule after the second pressing step.Another option is to have relatively small gel capsules mixed with theparticles of the invention and pressing the capsules together with thewhole mixture in one or more steps. However, an important aspect of theinvention is that the main part of the tableted chewing gum compositionoriginates from particulate material.

When a module of non-particulate matter is applied in the presentinvention, this would not be a layer in the sense of the invention.Hence, if a gel capsule is applied between two ‘layers’, the tabletedchewing gum composition would be annotated a two-layered chewing gumcomposition. Likewise, with a three-layered tableted chewing gumcomposition.

In another aspect of the invention, there is provided an intermediatechewing gum product for oral administration of cannabinoids, the productcomprising the chewing gum composition of the first aspect of theinvention as described on the previous pages. Importantly, this productmay comprise the particulate material according to the invention beforetableting. Also, the product may constitute the particulate materialaccording to the invention.

In another aspect of the invention, the chewing gum of the presentinvention may be used for the treatment or alleviation of a medicalcondition.

In certain embodiments of the invention, the chewing gum of the presentinvention may be used for the treatment or alleviation of a medicalcondition selected from the group consisting of pain, epilepsy, cancer,nausea, inflammation, congenital disorders, neurological disorders, oralinfections, dental pain, sleep apnea, psychiatric disorders,gastrointestinal disorders, inflammatory bowel disease, appetite loss,diabetes and fibromyalgia.

In the present context, the chewing gum of the invention may be appliedfor the medical indications as single indications from the list ofindications. The invention may also be applied for other medicalindications and indications that are not medical for instance localconditions in the mouth that may be treated or alleviated with theformulation of the present invention. The list is not exhaustive andother indications are part of the present invention.

In another aspect of the invention, a package is provided comprising achewing gum according to the invention, the package comprising amaterial acting as a barrier for the one or more cannabinoids andoxygen, preferably a copolymer of acrylonitrile and methyl acrylate.

In certain embodiments of the invention, the package includes a liquidor a semisolid for the provision of a preventive environment therein.

In certain embodiments of the invention, the package comprising achewing gum according to the invention, wherein the package is a blisterpackage.

FIGURES

FIGS. 1a and 1b illustrates a tableted chewing gum composition with onelayer,

FIGS. 2a and 2b illustrates a tableted chewing gum composition with twolayers,

FIGS. 3a and 3b illustrates a tableted chewing gum composition withthree layers,

FIGS. 4 and 5 illustrates a first and a second population of particles,and

FIG. 6 illustrates a first and a second population of particles in atableted chewing gum composition with two layers.

The invention will now be described in more details with reference toFIG. 1-6. These illustrations are intended to be understood inconnection with the rest of the description, including the Summary ofthe Invention, the Detailed Description and the Examples of theinvention.

FIG. 1a and FIG. 1b illustrates an embodiment of a tableted chewing gumcomposition 10 with a first layer 11. FIG. 1a is a cross-section of thetableted chewing gum composition and FIG. 1b illustrates the tabletedchewing gum composition seen from above. The tablet comprises an uppersurface and a bottom surface as well as a circular side surface.

FIG. 2a and FIG. 2b illustrates an embodiment of a tableted chewing gumcomposition 20 with two layers 21,22. FIG. 2a illustrates across-section of the tableted chewing gum composition and FIG. 2billustrates the tableted chewing gum composition seen from above. Thetablet comprises an upper surface and a bottom surface as well as acircular side surface. The tablet comprises a first layer 21 and asecond layer 22.

FIG. 3a and FIG. 3b illustrates an embodiment of a tableted chewing gumcomposition 30 with three layers 31,32,33. FIG. 3a illustrates across-section of the tableted chewing gum composition and FIG. 3billustrates the tableted chewing gum composition seen from above. Thetablet comprises an upper surface and a bottom surface as well as acircular side surface. The tablet comprises a first layer 33 and asecond layer 31 and a third layer 32.

FIG. 4 illustrates a closer view 40 of a cross-section of the firstlayer 11,21,33 of the tableted chewing gum compositions according toFIG. 1a-3a . In this embodiment, a first population of particles 41 ishomogeneously distributed with a second population of particles 42according to the invention. In this example the first and secondpopulation of particles are similar in size. The gum base content isillustrated with shadings of the first population of particles 41.

FIG. 5 illustrates a closer view 50 of a cross-section of the firstlayer 11,21,33 of the tableted chewing gum compositions according toFIG. 1a-3a . In this embodiment, a first population of particles 51 ishomogeneously distributed with a second population of particles 52according to the invention. In this example the particles of the firstpopulation of particles are larger in size than the particles of thesecond population of particles. The gum base content is illustrated withshadings of the first population of particles 51.

FIG. 6 illustrates a closer view 60 of a cross-section of the tabletedchewing gum compositions according to FIGS. 2a and 3a in theintersection between the individual layers 21,22 and 33,32. In thisembodiment, a first population of particles 61 is homogeneouslydistributed with a second population of particles 62 in layer 21,33whereas a second population of particles 63 is present in layer 22,32without presence of the first population of particles. The gum basecontent is illustrated with shadings of the first population ofparticles 61.

DETAILED DESCRIPTION OF THE INVENTION

The invention will now be described in more details with respect tocertain aspects and embodiments of the invention. These aspects andembodiments are intended to be understood in connection with the rest ofthe description, including the Summary of the Invention, the Figures andthe Examples of the invention.

The verb “to comprise” as is used in this description and in the claimsand its conjugations are used in its non-limiting sense to mean thatitems following the word are included, but items not specificallymentioned are not excluded. In addition, reference to an element by theindefinite article “a” or “an” does not exclude the possibility thatmore than one of the elements are present, unless the context clearlyrequires that there is one and only one of the elements. The indefinitearticle “a” or “an” thus usually means “at least one”. Additionally, thewords “a” and “an” when used in the present document in connection withthe word comprising or containing denote “one or more.” The expression“one or more” is intended to mean one, two, three or more.

In the present context the phrase “first population of particles”,“second population of particles” or “further populations of particles”refer to a distinct population of particles. The expression “first”,“second” or “third” is intended to mean that the individual populationshave different compositions, e.g. a “first” population may be a portionof particles that have a content of gum base whereas a “second”population may be a portion of particles that does not have a content ofgum base. However, if a “first” and “second” population is applied inone layer of a tablet, a “first” population in a second layer of thetablet may also have a different composition compared to a “first”population in the first layer. This may for instance be the case whenone type of sugar alcohol is applied as a “first population ofparticles” in one layer and another type of sugar alcohol is applied asa “first population of particles” in another layer. The intention withthe wording is mainly to distinguish two or more populations that areapplied together, for instance in a homogeneous mixture. The individualparticles in a “population” may comprise more than one ingredient, suchas for instance both water-insoluble gum base and water-soluble chewinggum ingredients, or other ingredients.

The term “population” as such is intended to mean a statisticalpopulation of particles characterized by a number of differentparameters, e.g. statistical parameters such as distribution ofparticles, average particle size, particle size distribution width, etc.Hence, a “population” may be a portion of particles characterized byhaving a normal distribution of particles with an average particle size,mean particles size and a distribution width. However, a “population”may also be a portion of particles that have undergone sieving where acertain lower or upper limit of particles size is present which does notnecessarily give a normal distribution of particles.

The term “particle size” relates to the ability of the particles to movethrough or be retained by sieve holes of a specific size. The content ofparticles having a particle size in a certain size range is provided asweight percent relative to the total weight of the particle populationin question. For instance, the population of particles having a contentof gum base may e.g. comprise 40% (w/w) particles having a size in therange of 500-800 microns and 60% (w/w) particles having a size in therange of 800-1400 microns. An average “particles size” is intended tomean a statistical average.

The term “plurality of particles” is intended to cover the “populationof particles” in the sense that the sum of populations are covered bythe term “plurality”.

The term “portion of particles” or similar wording is intended to mean aplurality of particles that collectively may comprise one or morepopulations of particles. For instance, a “portion of particles” may beapplied in a tableting apparatus and pressed into a first layer of atableted chewing gum composition. This layer may comprise one populationof particles or a “first population of particles”. However, this portionmay also comprise two “populations of particles”, etc.

The term “particle” or similar wording is intended to denote a single,discrete composition of solid matter, such as a granule or individualelements in powder, having a certain size that may deviate considerable.

By the terms “water-insoluble gum base” or “gum base” or “gum basematrix” or similar wording is meant the mainly water-insolubleingredients and hydrophobic gum base ingredients. The “gum base” maycontain gum base polymers and plasticizers, waxes, emulsifiers, fatsand/or fillers.

The term “water-soluble chewing gum ingredients” intends to mean themainly water-soluble and hydrophilic chewing gum ingredients.

The term “tableted” is intended to mean that the chewing gum compositionis pressed in a tableting apparatus and mainly being composed ofparticulate matter, such as one or more populations of particles orplurality of particles. Although the term “tableted” implies a methodstep, in the present context, the term is intended to mean the resultingtablet obtained in tableting a portion of particles. It is noted that atablet or tableted composition that is mentioned to comprise particleseventually is to be understood as particles that have been pressedtogether in a tableting step.

The term “weight of the chewing gum” or similar wording meaning the sameis defined in the present context as weight of the chewing gum, notincluding the weight of an outer coating, such as a hard coating, softcoating, and the like.

By the phrase “texture” is meant a qualitative measure of theviscoelastic properties of the chewing gum and of the overall mouth-feelexperienced by the user during the chewing process. Thus, the term“texture” encompasses measurable quantities such as hardness andelasticity as well as more subjective parameters related to thechew-feel experienced by a user.

The term “in vivo chewing” intends to mean that the chewing gum systemis chewed by a human subject in an experimental setup of trained testpersons according to statistically principles and that either the salivaof the human subject is subject to measurements or the chewed chewinggum is subject to measurements, the experimental setup being performedat a chewing frequency of 60 chews per minute.

The term “in vivo release” or “in vivo testing of release” or similarwording intends to mean that the chewing gum is tested according toExample 24.

The term “in vitro release” or “in vitro testing of release” or similarwording intends to mean that the chewing gum is tested according toExample 25, in particular according to Dissolution Test for ChewingGums, General Monograph 2.9.25 in European Pharmacopoeia, 5th ed.

The term “release” in the present context is intended to mean under “invitro” conditions if not stated otherwise. In particular, the “releaserate” during a certain period of time is intended to mean the amount inpercentage of cannabinoids that is released during the period at achewing frequency of 60 chews per minute.

The term “sustained release” or “extended release” is herein intended tomean prolonged release over time. The term “rapid release” or “quickrelease” or “high release” is herein intended to mean a higher contentreleased for a given period of time. The term “controlled release” isintended to mean a release of a substance from a gum by the aid ofactive chewing of the gum in the oral cavity of the subject, whereby theactive chewing is controlling the amount of substance released.

The term “delivery to the oral mucosa” or similar wording intends tomean that the chewing gum is tested according to Example 27.

A “self-emulsifying agent” is an agent which will form an emulsion whenpresented with an alternate phase with a minimum energy requirement. Incontrast, an emulsifying agent, as opposed to a self-emulsifying agent,is one requiring additional energy to form an emulsion.

The term “natural resin”, as used herein, means resinous compounds beingeither polyterpene derived from terpenes of natural origin or resinouscompounds derived from gum rosin, wood rosin or tall-oil rosin.

The gum base is the masticatory substance of the chewing gum, whichimparts the chew characteristics to the final product. The gum basetypically defines the release profile and plays a significant role inthe gum product. The gum base portion is retained in the mouththroughout the chew. The water-soluble portion disappears over a periodof time during chewing.

According to embodiments of the invention, a preferred amount of gumbase matrix in the final chewing gum is 30-75% by weight of the chewinggum before any optionally applied coating, such as 35-70% by weight ofthe chewing gum or 40-65% by weight of the chewing gum or 45-60% byweight of the chewing gum.

Elastomers provide the rubbery, elastomeric and bouncing nature to thegum, which varies depending on this ingredient's chemical structure andhow it may be compounded with other ingredients. Elastomers suitable foruse in the gum base and gum of the present invention may include naturalor synthetic types. Polyvinyl acetate elastomer plasticizers are notconsidered elastomers according to the invention.

Elastomers may be selected from the group consisting ofstyrene-butadiene copolymers, polyisobutylene, isobutylene-isoprenecopolymers, polyethylene, polyurethane or any combination thereof.Preferred elastomers are styrene-butadiene copolymers (SBR),polyisobutylene and isobutylene-isoprene copolymers (BR).

Styrene-butadiene type elastomers, or SBR as they may be called,typically are copolymers of from about 20:80 to 60:40 styrenes:butadienemonomers. The ratio of these monomers affects the elasticity of the SBRas evaluated by mooney viscosity. As the styrene:butadiene ratiodecreases, the mooney viscosity decreases.

The structure of SBR typically consists of straight chain 1,3-butadienecopolymerized with phenylethylene (styrene). The average molecularweight of SBR is <600,000 g/mole.

Isobutylene-isoprene type elastomers, or butyl as they may be called,have molar percent levels of isoprene ranging from 0.2 to 4.0. Similarto SBR, as the isoprene:isobutylene ratio decreases, so does theelasticity, measured by mooney viscosity.

The structure of butyl rubber typically consists of branched2-methyl-1,3-butadiene (isoprene) copolymerized with branched2-methylpropene (isobutylene). The average molecular weight of BR is inthe range from 150,000 g/mole to 1,000,000 g/mole.

Polyisobutylene, or PIB as they may be called, type elastomers arepolymers of 2-methylpropene. The low molecular weight elastomers providesoft chew characteristics to the gum base and still provide the elasticqualities as do the other elastomers. Average molecular weights mayrange from about 30,000 to 120,000 g/mole and the penetration may rangefrom about 4 millimeters to 20 millimeters. The higher the penetration,the softer the PIB. Similar to the SBR and butyl, the high molecularweight elastomers provide elasticity to the gum. Average molecularweight may range from 120,000 to 1,000,000 g/mole.

Polybutene range in average molecular weight from about 5.000 g/mole toabout 30.000 g/mole.

Useful natural elastomers include natural rubber such as smoked orliquid latex and guayule, natural gums such as jelutong, lechi caspi,perillo, sorva, massaranduba balata, massaranduba chocolate, nispero,rosidinha, chicle, gutta percha, gutta kataiu, niger gutta, tunu,chilte, chiquibul, gutta hang kang. Natural elastomers may also beapplied in aspects of the present invention.

Elastomer plasticizers vary the firmness of the gum base. Theirspecificity on elastomer inter-molecular chain breaking (plasticizing)along with their varying softening points cause varying degrees offinished gum firmness and compatibility when used in base. Polyvinylacetate elastomers plasticizers are examples of elastomer plasticizersof the present invention.

In some embodiments of the invention, the weight-average molecularweight (Mw) of the one or more polyvinyl acetate elastomer plasticizersis from 5,000 to 40,000. In some embodiments of the invention, theweight-average molecular weight (Mw) of the one or more polyvinylacetate elastomer plasticizers is from 6,000 to 35,000. In someembodiments of the invention, the weight-average molecular weight (Mw)of the one or more polyvinyl acetate elastomer plasticizers is from7,000 to 30,000. In some embodiments of the invention, theweight-average molecular weight (Mw) of the one or more polyvinylacetate elastomer plasticizers is from 8,000 to 25,000. In someembodiments of the invention, the weight-average molecular weight (Mw)of the one or more polyvinyl acetate elastomer plasticizers is from10,000 to 20,000.

In some embodiments of the invention, the viscosity of the one or morepolyvinyl acetate elastomer plasticizers is from 1.0 to 3.0 mPa*s asmeasured according to ASTM D445-06 (10 wt. % in ethyl acetate), such asfrom 1.0 to 2.5 mPa*s.

In some embodiments of the invention, the K value of the one or morepolyvinyl acetate elastomer plasticizers is from 15 to 33 as measuredaccording to DIN 53726 (1 wt. % in acetone), such as from 18 to 30.

Generally, the term “polyvinyl acetate elastomer plasticizer” isintended to mean polyvinyl acetate having a weight-average molecularweight (Mw) of less than about 40,000.

Generally, the term “polyvinyl acetate elastomer” is intended to meanpolyvinyl acetate having a weight-average molecular weight (Mw) of morethan about 40,000.

In certain embodiments of the invention, the gum base comprises lessthan 10% by weight of polyvinyl acetate elastomer. In certainembodiments of the invention, the gum base comprises less than 5% byweight of polyvinyl acetate elastomer. In certain embodiments of theinvention, the gum base comprises 2 to 6% by weight of polyvinyl acetateelastomer. In certain embodiments of the invention, the gum basecomprises 3 to 5% by weight of polyvinyl acetate elastomer. In certainembodiments of the invention, the gum base is substantially free ofpolyvinyl acetate elastomer.

In certain embodiments of the invention, the gum base comprises 15-35%by weight of the one or more polyvinyl acetate elastomer plasticizersand less than 10% by weight of polyvinyl acetate elastomer. In certainembodiments of the invention, the gum base comprises 15-35% by weight ofthe one or more polyvinyl acetate elastomer plasticizers and less than5% by weight of polyvinyl acetate elastomer. In certain embodiments ofthe invention, the gum base comprises 15-35% by weight of the one ormore polyvinyl acetate elastomer plasticizers and 2 to 6% by weight ofpolyvinyl acetate elastomer.

Natural resins may be selected from ester gums including as examplesglycerol esters of partially hydrogenated rosins, glycerol esters ofpolymerized rosins, glycerol esters of partially dimerized rosins,glycerol esters of tally oil rosins, pentaerythritol esters of partiallyhydrogenated rosins, methyl esters of rosins, partially hydrogenatedmethyl esters of rosins, pentaerythritol esters of rosins, syntheticresins such as terpene resins derived from alpha-pinene, beta-pinene,and/or d-limonene, and natural terpene resins.

In an embodiment of the invention, the chewing gum comprises furtherchewing gum ingredients selected from the group consisting of flavors,dry-binders, tableting aids, anti-caking agents, emulsifiers,antioxidants, enhancers, mucoadhesives, absorption enhancers, highintensity sweeteners, softeners, colors, active ingredients,water-soluble indigestible polysaccharides, water-insolublepolysaccharides or any combination thereof.

According to embodiments of the invention, the emulsifiers may beselected from the group consisting of sucrose ester of fatty acids (suchas sucrose mono stearate), polyethylene glycol esters or ethers (PEG)(such as caprylocaproyl macrogol-8 glycerides and lauroylmacrogol-32-glycerides), mono- and diglyceride of fatty acids (such asglycerol monostearate, glycerol monolaurate, glyceryl behenate ester),acetic acid esters of mono- and diglycerides of fatty acids (Acetem),polyoxyethylene alkyl ethers, diacetyl tartaric ester of monoglycerides,lactylated monoglycerides, glycerophospholipids (such as lecithin),poloxamer (non-ionic block copolymer of ethylene oxide and propyleneoxide), cyclodextrins, fatty acid esters of sorbitol (such as sorbitanmonolaurate, sorbitan monostearate, sorbitan tristearate, polysorbates).Self-emulsifying emulsifiers may be phospholipids (Lecithin),Polysorbates (polysorbate 80).

SEDDS (self-emulsifying drug delivery system) may consist of hard orsoft capsules filled with a liquid or a gel that consists ofself-emulsifiers, one or more cannabinoids, oil (to dissolve thecannabinoids) and a surfactant. SEDDS may comprise of a blend or mixtureof self-emulsifiers, one or more cannabinoids, oil (to dissolve thecannabinoids) and a surfactant. SEDDS may comprise granules comprisingself-emulsifiers, one or more cannabinoids, oil (to dissolve thecannabinoids) and a surfactant. Upon contact with gastric fluid, theSEDDS spontaneously emulsify due to the presence of surfactants. Manysurfactants, however, are lipid based and interact with lipases in theGIT (gastro intestinal tract). This can lead to a reduced capability ofthe lipid-based surfactants to emulsify the one or more cannabinoids aswell as the oil carrier, both reducing bioavailability.

According to embodiments of the invention, flavors may be selected fromthe group consisting of coconut, coffee, chocolate, vanilla, grapefruit, orange, lime, menthol, liquorice, caramel aroma, honey aroma,peanut, walnut, cashew, hazelnut, almonds, pineapple, strawberry,raspberry, tropical fruits, cherries, cinnamon, peppermint, wintergreen,spearmint, eucalyptus, and mint, fruit essence such as from apple, pear,peach, strawberry, apricot, raspberry, cherry, pineapple, and plumessence. The essential oils include peppermint, spearmint, menthol,eucalyptus, clove oil, bay oil, anise, thyme, cedar leaf oil, nutmeg,and oils of the fruits mentioned above.

Petroleum waxes aid in the curing of the finished gum made from the gumbase as well as improve shelf life and texture. Wax crystal sizeinfluences the release of flavor. Those waxes high in iso-alkanes have asmaller crystal size than those waxes high in normal-alkanes, especiallythose with normal-alkanes of carbon numbers less than 30. The smallercrystal size allows slower release of flavor since there is morehindrance of the flavor's escape from this wax versus a wax havinglarger crystal sizes.

Petroleum wax (refined paraffin and microcrystalline wax) and paraffinwax are composed of mainly straight-chained normal-alkanes and branchediso-alkanes. The ratio of normal-alkanes to iso-alkanes varies.

Antioxidants prolong shelf life and storage of gum base, finished gum ortheir respective components including fats and flavor oils.

Antioxidants suitable for use in gum base include butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), betacarotenes,tocopherols, acidulants such as Vitamin C (ascorbic acid orcorresponding salts (ascorbates)), propyl gallate, catechins, othersynthetic and natural types or mixtures thereof.

Further chewing gum ingredients, which may be included in the chewinggum according to the present invention, include surfactants and/orsolubilizers. As examples of types of surfactants to be used assolubilizers in a chewing gum composition according to the invention,reference is made to H. P. Fiedler, Lexikon der Hilfstoffe fürPharmacie, Kosmetik and Angrenzende Gebiete, pages 63-64 (1981) and thelists of approved food emulsifiers of the individual countries. Anionic,cationic, amphoteric or non-ionic solubilizers can be used. Suitablesolubilizers include lecithin, polyoxyethylene stearate, polyoxyethylenesorbitan fatty acid esters, fatty acid salts, mono and diacetyl tartaricacid esters of mono and diglycerides of edible fatty acids, citric acidesters of mono and diglycerides of edible fatty acids, saccharose estersof fatty acids, polyglycerol esters of fatty acids, polyglycerol estersof interesterified castor oil acid (E476), sodium stearoyllatylate,sodium lauryl sulfate and sorbitan esters of fatty acids andpolyoxyethylated hydrogenated castor oil (e.g. the product sold underthe trade name CREMOPHOR), block copolymers of ethylene oxide andpropylene oxide (e.g. products sold under trade names PLURONIC andPOLOXAMER), polyoxyethylene fatty alcohol ethers, polyoxyethylenesorbitan fatty acid esters, sorbitan esters of fatty acids andpolyoxyethylene steraric acid esters.

Particularly suitable solubilizers are polyoxyethylene stearates, suchas for instance poly-oxyethylene(8)stearate andpolyoxyethylene(40)stearate, the polyoxyethylene sorbitan fatty acidesters sold under the trade name TWEEN, for instance TWEEN 20(monolaurate), TWEEN 80 (monooleate), TWEEN 40 (monopalmitate), TWEEN 60(monostearate) or TWEEN 65 (tristearate), mono and diacetyl tartaricacid esters of mono and diglycerides of edible fatty acids, citric acidesters of mono and diglycerides of edible fatty acids, sodiumstearoyllatylate, sodium laurylsulfate, polyoxyethylated hydrogenatedcastor oil, blockcopolymers of ethylene oxide and propyleneoxide andpolyoxyethylene fatty alcohol ether. The solubilizer may either be asingle compound or a combination of several compounds. In the presenceof an active ingredient, such as the included one or more cannabinoids,the chewing gum may preferably also comprise a carrier known in the artsof chewing gum and active ingredients. Poloxamer F68 is a further highlysuitable solubilizer.

High intensity artificial sweetening agents can also be used accordingto preferred embodiments of the invention. Preferred high intensitysweeteners include, but are not limited to sucralose, aspartame, saltsof acesulfame, alitame, neotame, saccharin and its salts, cyclamic acidand its salts, glycyrrhizin, dihydrochalcones, thaumatin, monellin, monkfruit extract, advantame, stevioside and the like, alone or incombination.

In order to provide longer lasting sweetness and flavor perception, itmay be desirable to encapsulate or otherwise control the release of atleast a portion of the artificial sweeteners.

Techniques such as wet granulation, wax granulation, spray drying, spraychilling, fluid bed coating, conservation, encapsulation in yeast cellsand fiber extrusion may be used to achieve desired releasecharacteristics. Encapsulation of sweetening agents can also be providedusing another chewing gum component such as a resinous compound.

Usage level of the high-intensity sweetener will vary considerably andwill depend on factors such as potency of the sweetener, rate ofrelease, desired sweetness of the product, level and type of flavor usedand cost considerations. Thus, the active level of artificial sweetenermay vary from about 0.001 to about 8% by weight (preferably from about0.02 to about 8% by weight). When carriers used for encapsulation areincluded, the usage level of the encapsulated high-intensity sweetenerwill be proportionately higher.

A chewing gum and/or gum base may, if desired, include one or morefillers/texturizers including as examples, magnesium- and calciumcarbonate, sodium sulphate, ground limestone, silicate compounds such asmagnesium- and aluminum silicate, kaolin and clay, aluminum oxide,silicium oxide, talc, titanium oxide,

mono-, di- and tri-calcium phosphates, cellulose polymers, such as wood,and combinations thereof. According to an embodiment of the invention,one preferred filler/texturizer is calcium carbonate.

A number of chewing gum components well known within the art may beapplied within the scope of the present invention. Such componentscomprise but are not limited to waxes, fats, softeners, fillers, bulksweeteners, flavors, antioxidants, emulsifiers, coloring agents, bindingagents and acidulants.

In an embodiment of the invention, water-soluble ingredients comprise atleast one sugar alcohol. The at least one sugar alcohol may be selectedfrom the group consisting of xylitol, sorbitol, mannitol, maltitol,isomaltitol, isomalt, erythritol, lactitol, maltodextrin, hydrogenatedstarch hydrolysates, and combinations thereof.

A specific example of one category of polyol sweeteners include sugars,in particular a sugar selected from the group consisting of dextrose,sucrose, maltose, fructose, lactose, and combinations thereof.

A method of manufacturing tableted chewing gum according to theinvention may be as follows:

Gum bases are typically prepared by adding an amount of the elastomer,elastomer plasticizer and filler to a heated (100° C.-120° C.) sigmablade mixer with a front to rear speed ratio of from about 1.2:1 toabout 2:1, the higher ratio typically being used for gum base whichrequires more rigorous compounding of its elastomers.

The initial amounts of ingredients comprising the initial mass may bedetermined by the working capacity of the mixing kettle in order toattain a proper consistency and by the degree of compounding desired tobreak down the elastomer and increase chain branching. The higher thelevel of filler at the start or selection of a filler having a certainparticle size distribution, the higher the degree of compounding andthus more of the elastomeric chain crosslinking are broken, causing morebranching of the elastomer thus lower viscosity gum bases and thussofter final gum base and gum made from such a gum base. The longer thetime of compounding, the use of lower molecular weight or softeningpoint gum base ingredients, the lower the viscosity and firmness of thefinal gum base.

Compounding typically begins to be effective once the ingredients havemassed together. Anywhere from 15 minutes to 90 minutes may be thelength of compounding time.

Preferably, the time of compounding is from 20 minutes to about 60minutes. The amount of added elastomer plasticizer depends on the levelof elastomer and filler present. If too much elastomer plasticizer isadded, the initial mass becomes over plasticized and not homogeneous.

After the initial ingredients have massed homogeneously and compoundedfor the time desired, the balance of the gum base ingredients are addedin a sequential manner until a completely homogeneous molten mass isattained. Typically, any remainder of elastomer, elastomer plasticizerand filler, are added within 60 minutes after the initial compoundingtime. The filler and the elastomer plasticizer would typically beindividually weighed and added in portions during this time. Theoptional waxes, softeners and antioxidants are typically added after theelastomer and elastomer plasticizers and during the next 60 minutes.Then the mass is allowed to become homogeneous before dumping.

Typical gum base processing times may vary from about one to about threehours, preferably from about 1½ to 2½ hours, depending on theformulation. The final mass temperature when dumped may be between 70°C. and 130° C. and preferably between 100° C. and 120° C. The completedmolten mass is emptied from the mixing kettle into coated or lined pans,extruded or cast into any desirable shape and allowed to cool andsolidify. Those skilled in the art will recognize that many variationsof the above described procedure may be followed.

The gum base (or gum composition) may be further processed in anextruder where the gum composition is extruded through a die plate intoa liquid filled chamber, resulting in particles directly applicable fortableting. Alternatively, the gum base may be milled into a desiredparticle range.

The water-soluble chewing gum ingredients of the tableted chewing gummay comprise softeners, sweeteners, high intensity sweeteners, flavoringagents, acidulants, fillers, antioxidants, and other components thatprovide desired attributes. Softeners typically constitute from about0.5% to about 25.0% by weight of the chewing gum. The bulking agentsgenerally comprise from about 5% to about 90%, preferably from about 20%to about 80% of the chewing gum. High-intensity sweeteners in gumtypically may range from about 0.01 to 0.50 weight percent. Flavoringagents may be present in the chewing gum in an amount within the rangeof from about 0.1 to about 15.0 weight percent of the gum.

The water-soluble chewing gum ingredients of the tableted chewing gumcomposition according to the invention may be part of the firstpopulation of particles and subsequently subject to further processingin an extruder where the gum composition is extruded through a die plateinto a liquid filled chamber, before tableting. However, thewater-soluble chewing gum ingredients may also be part of a secondpopulation of particles or further populations of particles that are notexposed to a liquid filled chamber but applied together with the firstpopulation of particles to a tableting apparatus. In yet anotherembodiments, the water-soluble chewing gum ingredients may be part ofthe particles comprising water-insoluble gum base and not exposed to aliquid filled chamber but used directly in a tableting apparatus,optionally together with additional separate ingredients.

In an embodiment of the invention, the first population of particles,comprising water-insoluble gum base, has an average diameter in therange from 0.1 to 2.5 mm.

In an embodiment of the invention, the first population of particles,comprising water-insoluble gum base, has an average diameter in therange from 0.3 to 2.1 mm.

In an embodiment of the invention, the first population of particles,comprising water-insoluble gum base, has an average diameter in therange from 0.8 to 1.4 mm.

The tableted chewing gum composition according to the invention ismanufactured by applying pressure to a content of particles by suitablecompression means. The particles or powder is then pressed into acompact coherent tablet. The particles may for example compriseso-called primary particles or aggregated primary particles. When theseare pressed, bonds are established between the particles or granules,thereby conferring a certain mechanical strength to the pressed tablet.

It should be noted that the above-introduced terms: powder, primaryparticles and aggregated primary particles may be somewhat misleading inthe sense that the difference between primary particles and aggregatedprimary particles may very often be looked upon differently depending onthe background of the user. Some may for instance regard a sweetener,such as sorbitol, as a primary particle in spite of the fact thatsorbitol due to the typically preprocessing performed on sorbitol whendelivered to the customer should rather be regarded as some sort ofaggregated primary particles. The definition adopted in the descriptionof this invention is that aggregated primary particles refer tomacro-particles comprising more or less preprocessed primary particles.

When pressure is applied to the particles, the bulk volume is reduced,and the amount of air is decreased. During this process energy isconsumed. As the particles come into closer proximity to each otherduring the volume reduction process, bonds may be established betweenthe particles or granules. The formation of bonds is associated with areduction in the energy of the system as energy is released. Volumereduction takes place by various mechanisms and different types of bondsmay be established between the particles or granules depending on thepressure applied and the properties of the particles or granules. Thefirst thing that happens when a powder is pressed is that the particlesare rearranged under low compaction pressures to form a closer packingstructure. Particles with a regular shape appear to undergorearrangement more easily than those of irregular shape. As the pressureincreases, further rearrangement is prevented, and subsequent volumereduction is obtained by plastic and elastic deformation and/orfragmentation of the tablet particles. Brittle particles are likely toundergo fragmentation, i.e. breakage of the original particles intosmaller units. Plastic deformation is an irreversible process resultingin a permanent change of particle shape, whereas the particles resumetheir original shape after elastic deformation. Evidently, both plasticand elastic deformation may occur, when compressing a chewing gumtablet.

Several studies of the bond types in pressed tablets have been made overthe years, typically in the context of pharmaceuticals and severaltechniques of obtaining pressed tablets on the basis of availablepowders has been provided. Such studies have been quite focused on whathappens when the volume reduction is performed and how the end-productmay be optimized for the given purpose. Several refinements with respectto pressed tablets has for instance been made in the addition of forexample binders in the tablet raw materials for the purpose of obtaininga sufficient strength to the final pressed tablet while maintainingacceptable properties, e.g. with respect to release.

Contrary to the tableted chewing gum composition according to theinvention, conventional chewing gum (which is mentioned here forreference purposes) may be manufactured by sequentially adding thevarious chewing gum ingredients to a commercially available mixer knownin the art where the finished gum base is already present. After theinitial ingredients have been thoroughly mixed, the gum mass isdischarged from the mixer and shaped into the desired form such as byrolling into sheets and cutting into sticks, extruded into chunks orcasting into pellets. Generally, the ingredients of conventional chewinggum may be mixed by first melting the gum base and adding it to therunning mixer. Colors, active agents and/or emulsifiers may also beadded at this time. A softener such as glycerin may also be added atthis time, along with syrup and a portion of the bulkingagent/sweetener. Further portions of the bulking agent/sweetener maythen be added to the mixer. A flavoring agent is typically added withthe final portion of the bulking agent/sweetener. A high-intensitysweetener is preferably added after the final portion of bulking agentand flavor have been added. The entire mixing procedure typically takesfrom thirty to forty minutes, but longer mixing times may sometimes berequired. Those skilled in the art will recognize that many variationsof the above described procedure may be followed.

In accordance with the invention, the tableted chewing gum according tothe invention may comprise about 0.1 to about 75% by weight of an outercoating applied onto the chewing gum centre. Thus, suitable coatingtypes include hard coatings, film coatings and soft coatings of anycomposition including those currently used in coating of tabletedchewing gum.

One presently preferred outer coating type is a hard coating, which termis used in the conventional meaning of that term including sugarcoatings and sugar-free (or sugarless) coatings and combinationsthereof. The object of hard coating is to obtain a sweet, crunchy layer,which is appreciated by the consumer and it may moreover protect the gumcentres for various reasons. In a typical process of providing thechewing gum centres with a protective sugar coating, the gum centres aresuccessively treated in suitable coating equipment with aqueoussolutions of crystallisable sugar such as sucrose or dextrose, which,depending on the stage of coating reached, may contain other functionalingredients, e.g. fillers, binding agents, colours, etc. In the presentcontext, the sugar coating may contain further functional or activecompounds including flavour compounds and/or active compounds.

In a typical hard coating process as it will be described in detail inthe following, a suspension containing crystallisable sugar and/orpolyol is applied onto the gum centres and the water it contains isevaporated off by blowing with air. This cycle must be repeated severaltimes, typically 3 to 80 times, in order to reach the swelling required.The term “swelling” refers to the increase in weight or thickness of theproducts, as considered at the end of the coating operation bycomparison with the beginning, and in relation to the final weight orthickness of the coated products. In accordance with the presentinvention, the coating layer constitutes about 0.1 to about 75% byweight of the finished chewing gum element, such as about 10 to about60% by weight, including about 15 to about 50% by weight.

In further useful embodiments, the outer coating of the chewing gumelement of the invention is an element that is subjected to a filmcoating process and which therefore comprises one or more film-formingpolymeric agents and optionally one or more auxiliary compounds, e.g.plasticizers, pigments and opacifiers. A film coating is a thinpolymer-based coating applied to a chewing gum centre of any of theabove forms. The thickness of such a coating is usually between 20 and100 μm.

Generally, the film coating is obtained by passing the chewing gumcentres through a spray zone with atomized droplets of the coatingmaterials in a suitable aqueous or organic solvent vehicle, after whichthe material adhering to the gum centres is dried before the nextportion of coating is received. This cycle is repeated until the coatingis complete.

In the present context, suitable film-coating polymers include ediblecellulose derivatives such as cellulose ethers including methylcellulose(MC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC) andhydroxypropyl methylcellulose (HPMC). Other useful film-coating agentsare acrylic polymers and copolymers, e.g. methylacrylate aminoestercopolymer or mixtures of cellulose derivatives and acrylic polymers. Aparticular group of film-coating polymers, also referred to asfunctional polymers are polymers that, in addition to its film-formingcharacteristics, confer a modified release performance with respect toactive components of the chewing gum formulation. Such release modifyingpolymers include methylacrylate ester copolymers, ethylcellulose (EC)and enteric polymers designed to resist the acidic stomach environment.The latter group of polymers include: cellulose acetate phtalate (CAP),polyvinyl acetate phtalate (PVAP), shellac, metacrylic acid copolymers,cellulose acetate trimellitate (CAT) and HPMC. It will be appreciatedthat the outer film coating according to the present invention maycomprise any combination of the above film-coating polymers.

According to the invention, the one or more cannabinoids may be selectedfrom various cannabinoids.

“Cannabinoids” are a group of compounds including the endocannabinoids,the phytocannabinoids and those which are neither endocannabinoids orphytocannabinoids, hereinafter “syntho-cannabinoids”.

“Endocannabinoids” are endogenous cannabinoids, which may have highaffinity ligands of CB1 and CB2 receptors.

“Phytocannabinoids” are cannabinoids that originate in nature and can befound in the cannabis plant. The phytocannabinoids can be present in anextract including a botanical drug substance, isolated, or reproducedsynthetically.

“Syntho-cannabinoids” are those compounds capable of interacting withthe cannabinoid receptors (CB1 and/or CB2) but are not foundendogenously or in the cannabis plant. Examples include WIN 55212 andrimonabant.

An “isolated phytocannabinoid” is one which has been extracted from thecannabis plant and purified to such an extent that the additionalcomponents such as secondary and minor cannabinoids and thenon-cannabinoid fraction have been substantially removed.

A “synthetic cannabinoid” is one which has been produced by chemicalsynthesis. This term includes modifying an isolated phytocannabinoid,by, for example, forming a pharmaceutically acceptable salt thereof.

A “substantially pure” cannabinoid is defined as a cannabinoid which ispresent at greater than 95% (w/w) pure. More preferably greater than 96%(w/w) through 97% (w/w) thorough 98% (w/w) to 99% % (w/w) and greater.

A “highly purified” cannabinoid is defined as a cannabinoid that hasbeen extracted from the cannabis plant and purified to the extent thatother cannabinoids and non-cannabinoid components that are co-extractedwith the cannabinoids have been substantially removed, such that thehighly purified cannabinoid is greater than or equal to 95% (w/w) pure.

“Plant material” is defined as a plant or plant part (e.g. bark, wood,leaves, stems, roots, flowers, fruits, seeds, berries or parts thereof)as well as exudates, and includes material falling within the definitionof “botanical raw material” in the Guidance for Industry Botanical DrugProducts Draft Guidance, August 2000, US Department of Health and HumanServices, Food and Drug Administration Center for Drug Evaluation andResearch.

In the context of this application the terms “cannabinoid extract” or“extract of cannabinoids”, which are used interchangeably, encompass“Botanical Drug Substances” derived from cannabis plant material. ABotanical Drug Substance is defined in the Guidance for IndustryBotanical Drug Products Draft Guidance, August 2000, US Department ofHealth and Human Services, Food and Drug Administration Centre for DrugEvaluation and Research as: “A drug substance derived from one or moreplants, algae, or macroscopic fungi. It is prepared from botanical rawmaterials by one or more of the following processes:

pulverisation, decoction, expression, aqueous extraction, ethanolicextraction, or other similar processes.” A botanical drug substance doesnot include a highly purified or chemically modified substance derivedfrom natural sources. Thus, in the case of cannabis, “botanical drugsubstances” derived from cannabis plants do not include highly purified,Pharmacopoeial grade cannabinoids.

The term “Cannabis plant(s)” encompasses wild type Cannabis sativa andalso variants thereof, including cannabis chemovars which naturallycontain different amounts of the individual cannabinoids, Cannabissativa subspecies indica including the variants var. indica and var.kafiristanica, Cannabis indica, Cannabis ruderalis and also plants whichare the result of genetic crosses, self-crosses or hybrids thereof. Theterm “Cannabis plant material” is to be interpreted accordingly asencompassing plant material derived from one or more cannabis plants.For the avoidance of doubt it is hereby stated that “cannabis plantmaterial” includes dried cannabis biomass.

Preferably the one or more cannabinoids are selected from:cannabichromene (CBC), cannabichromenic acid (CBCV), cannabidiol (CBD),cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG),cannabigerol propyl variant (CBGV), cannabicyclol (CBL), cannabinol(CBN), cannabinol propyl variant (CBNV), cannabitriol (CBO),tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA),tetrahydrocannabivarin (THCV) and tetrahydrocannabivarinic acid (THCVA). More preferably the one or more cannabinoid is CBD or THC. This listis not exhaustive and merely details the cannabinoids which areidentified in the present application for reference.

So far, more than 120 different phytocannabinoids have been identifiedwhich are within the scope of the present invention.

Cannabinoids can be split into different groups as follows:Phytocannabinoids;

Endocannabinoids; and Synthetic cannabinoids.

Cannabinoid receptors can be activated by three major groups of agonistligands, for the purposes of the present invention and whether or notexplicitly denominated as such herein, lipophilic in nature and classedrespectively as: endocannabinoids (produced endogenously by mammaliancells); phytocannabinoids (such as cannabidiol, produced by the cannabisplant); and, synthetic cannabinoids (such as HU-210).

Phytocannabinoids can be found as either the neutral carboxylic acidform or the decarboxylated form depending on the method used to extractthe cannabinoids. For example, it is known that heating the carboxylicacid form will cause most of the carboxylic acid form to decarboxylate.

Phytocannabinoids can also occur as either the pentyl (5 carbon atoms)or propyl (3 carbon atoms) variant. For example, the phytocannabinoidTHC is known to be a CB1 receptor agonist whereas the propyl variantTHCV has been discovered to be a CB1 receptor antagonist meaning that ithas almost opposite effects.

According to the invention, examples of phytocannabinoids may becannabichromene (CBC), cannabichromenic acid (CBCV), cannabidiol (CBD),cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG),cannabigerol propyl variant (CBGV), cannabicyclol (CBL), cannabinol(CBN), cannabinol propyl variant (CBNV), cannabitriol (CBO),tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA),tetrahydrocannabivarin (THCV) and tetrahydrocannabivarinic acid (THCVA). More preferably the one or more cannabinoid is CBD or THC.

The formulation according to the present invention may also comprise atleast one cannabinoid selected from those disclosed in A. DouglasKinghorn et al., Phytocannabinoids, Vol. 103, Chapter 1, pages 1-30.

Examples of endocannabinoids are molecules that activate the cannabinoidreceptors within the body. Examples include 2-arachidonyl glycerol(2AG), 2-arachidonyl glyceryl ether (2AGE), arachidonyl dopamine, andarachidonyl ethanolamide (anandamide). Structurally related endogenousmolecules have been identified that share similar structural features,but that display weak or no activity towards the cannabinoid receptorsbut are also termed endocannabinoids.

Examples of these endocannabinoid lipids include 2-acyl glycerols, alkylor alkenyl glyceryl ethers, acyl dopamines and N-acylethanolamides thatcontain alternative fatty acid or alcohol moieties, as well as otherfatty acid amides containing different head groups. These includeN-acylserines as well as many other N-acylated amino acids. Examples ofcannabinoid receptor agonists are neuromodulatory and affect short-termmemory, appetite, stress response, anxiety, immune function andanalgesia.

In one embodiment the cannabinoid is palmitoylethanolamide (PEA) whichis an endogenous fatty acid amide belonging to the class of nuclearfactor agonists.

Synthetic cannabinoids encompass a variety of distinct chemical classes:the cannabinoids structurally related to THC, the cannabinoids notrelated to THC, such as (cannabimimetics) including theaminoalkylindoles, 1,5-diarylpyrazoles, quinolines, and arylsulfonamides, and eicosanoids related to the endocannabinoids. All orany of these cannabinoids can be used in the present invention.

It is preferred that the formulation comprises one or two primarycannabinoids, which are preferably selected from the group consistingof, cannabidiol (CBD) or cannabidivarin (CBDV), tetrahydrocannabinol(THC), tetrahydrocannabivarin (THCV), tetrahydrocannabinolic acid(THCA), cannabigerol (CBG) and cannabidiolic acid (CBDA) or acombination thereof. It is preferred that the formulation comprisescannabidiol and/or tetrahydrocannabinol.

Preferably, the chewing gum of the present invention may be used for thetreatment or alleviation of pain, epilepsy, cancer, nausea,inflammation, congenital disorders, neurological disorders, oralinfections, dental pain, sleep apnea, psychiatric disorders,gastrointestinal disorders, inflammatory bowel disease, appetite loss,diabetes and fibromyalgia.

In a further aspect of the present invention the oral cannabinoidformulation is suitable for use in the treatment of conditions requiringthe administration of a neuroprotectant or anti-convulsive medication.

The oral cannabinoid formulation may be for use in the treatment ofseizures.

The oral cannabinoid formulation may be for use in the treatment ofDravet syndrome, Lennox Gastaut syndrome, myoclonic seizures, juvenilemyoclonic epilepsy, refractory epilepsy, schizophrenia, juvenile spasms,West syndrome, infantile spasms, refractory infantile spasms, tuberoussclerosis complex, brain tumours, neuropathic pain, cannabis usedisorder, post-traumatic stress disorder, anxiety, early psychosis,Alzheimer's disease, and autism.

The following non-limiting examples illustrate different variations ofthe present invention. The examples are meant for indicating theinventive concept; hence the mentioned examples should not be understoodas exhaustive for the present. In particular, CBD is used as anexemplary compound, but may also be another cannabinoid.

EXAMPLES Example 1

A: Preparation of Water Insoluble Gum Base Particles

Twenty different water-insoluble gum base compositions were prepared.The gum base compositions were prepared in the process as describedbelow. In subsequent examples, the specific compositions of the gumbases (GB10 to GB29) are outlined.

In all of the gum base examples, the amount of the various ingredientsis given as % by weight of the gum base.

Elastomers and elastomer plasticizer (PVA) were mixed at 120° C.together with filler, either calcium carbonate or talc, in a mixerhaving horizontally placed Z-shaped arms for mixing. It is noted thatPVA was applied as an elastomer plasticizer for the elastomers in thecomposition and not in form of an elastomer. PVA as an elastomerplasticizer has special properties in the present context. For some ofthe comparative examples, another comparative polymer was added togetherwith the elastomers and elastomer plasticizer and mixed together withthe elastomer and the elastomer plasticizer. Natural resins were addedafter about 30 minutes of mixing of the polymers. Once the polymers andthe natural resins had softened in the composition, additionalingredients were added, such as triacetin, emulsifier, wax,antioxidants, calcium carbonate, talc, titan dioxide and vegetable fat.A part of the calcium carbonate or talc may be substituted by titandioxide.

After a total mixing time of about 90-105 minutes, the mixture wasdischarged into a pan and allowed to cool at room temperature. For someof the examples where butyl rubber (BR) was added as an elastomer, themixing time was optionally extended to a total of about 110-115 minutesdepending on the amount of optional fillers.

The gum compositions were further processed in an extruder (LeistritsZSE/BL 360 kw 104, available from GALA GmbH, Germany). The gumcompositions were extruded through a die plate into a liquid filledchamber (granulator A5 PAC 6, available from GALA GmbH, Germany).

The extruder delivered the composition at a feed rate of 250 kg/h to thedie plate. The extruder screw speed was 247 rpm. The temperature in theextruder was about 80° C. and was mainly regulated by the temperature ofthe gum compositions that were only allowed to cool slightly prior tobeing introduced into the extruder. The extruder produced a pressuredifference of 71 bar.

The gum composition was extruded through the die plate, which was heatedto a temperature of 177° C. and had 336 holes with diameter 0.36 mm. Inthe granulator chamber the extruded composition was cut to particles bya cutter with 8 blades and cutter speed about 2000 rpm. The particleswere cooled and transported to a strainer unit (a centrifugal dryer TWS20, available from GALA GmbH, Germany) in water with temperature about10° C. and flow 22 m³/h. The average cooling and transport time in waterwas approx. 2 seconds. The granule rate was 250 kg/h and the averagediameter of the obtained particles was 1.24 mm. The particles correspondto a first population of particles comprising water-insoluble gum base.These particles were used for tableting.

Example 2

Various Gum Base Formulations

TABLE 1A Gum base compositions, PVA = polyvinyl acetate (Vinnapas B 1.5sp., supplied by Wacker); PIB = polyisobutylene (Oppanol B12, suppliedby BASF); BR = butyl rubber (isobutylene-isoprene copolymer); Nat. resin= glycerol ester of hydrogenated gum rosin; Veg. fat = vegetable fat. GBnumber GB10 GB11 GB12 GB13 GB14 PVA 25 18 30 10 40 PIB 5 10 5 10 5 BR 55 5 5 — Nat. 25 20 20 35 15 resin Calcium 17 — 17 17 17 Carbonate Talc —17 — — — Triacetin — 7 — — — Emulsifier 5 10 5 5 5 Wax 13 13 13 13 13Veg. fat 5 — 5 5 5 Total 100 100 100 100 100

Example 3

Various Gum Base Formulations

TABLE 1B GB number GB15 GB16 GB17 GB18 GB19 PVA 25 25 20 40 15 PIB 5 105 5 5 BR 5 5 5 5 — Nat. 25 20 30 10 40 resin Calcium 17 17 17 17 17Carbonate Talc — — — — — Triacetin — — — — — Emulsifier 5 5 5 5 5 Wax 1313 13 13 13 Veg. fat 5 5 5 5 5 Total 100 100 100 100 100 Gum basecompositions, PVA = polyvinyl acetate (Vinnapas B 1.5 sp., supplied byWacker); PIB = polyisobutylene (Oppanol B12, supplied by BASF); BR =butyl rubber (isobutylene-isoprene copolymer); Nat. resin = glycerolester of hydrogenated gum rosin; Veg. fat = vegetable fat.

Example 4

Various Gum Base Formulations

TABLE 1C GB number GB20 GB21 GB22 GB23 GB24 PVA 18 18 18 18 18 PIB 10 1010 10 10 BR 5 5 5 5 5 Nat. 20 20 20 20 20 resin Calcium — — — — —Carbonate Talc 14 16.5 13.5 17 14 Triacetin 7 7 7 7 7 Emulsifier 10 1010 10 10 Wax 13 13 13 13 13 Veg. fat — — — — — Acesulfame — 0.5 0.5 — —K Menthol 3 — 3 — 3 BHT — — — 0.04 0.04 Total 100 100 100 100 100 Gumbase compositions, PVA = polyvinyl acetate (Vinnapas B 1.5 sp., suppliedby Wacker); PIB = polyisobutylene (Oppanol B12, supplied by BASF); BR =butyl rubber (isobutylene-isoprene copolymer); Nat. resin = glycerolester of hydrogenated gum rosin; Veg. fat = vegetable fat; Acesulfame K(HIS = high-intensity sweetener); Menthol (flavor); BHT (Butylatedhydroxytoluene = antioxidant).

Example 5

Various Gum Base Formulations

TABLE 1D GB number GB25 GB26 GB27 GB28 GB29 PVA 25 18 30 30 20 PIB 5 105 3 3 BR 5 5 — 2 2 Nat. 25 20 — — 20 resin VA-VL — — 20 20 10 Calcium 17— 17 17 17 Carbonate Talc — 17 — — — Triacetin — 7 — — 2 Emulsifier 5 1011 11 9 Wax 13 13 12 12 12 Veg. fat 5 — 5 5 5 Total 100 100 100 100 100Gum base compositions, PVA = polyvinyl acetate (Vinnapas B 1.5 sp.,supplied by Wacker); PIB = polyisobutylene (Oppanol B12, supplied byBASF); BR = butyl rubber (isobutylene-isoprene copolymer); Nat. resin =glycerol ester of hydrogenated gum rosin; VA-VL = vinyl acetate-vinyllaurate copolymer (Vinnapas B 500/40VL, supplied by Wacker); Veg. fat =vegetable fat.

Example 6

CBD Extract 52%

CBD extract with a 52% content of CBD provided by CBDepot (batch numberCSFF 2018/5) was preheated to around 60° C. for around 0.5 to 1 houruntil the extract was in liquid form. The extract had a content of fattyacids, glycerol, waxes, terpenes and flavonoids. After the preheatingprocess, the extract was applied as a thin layer on top of one or moresugar alcohol particles, here isomalt. After mixing until CBD washomogeneously distributed in the isomalt, the mixture was sieved througha 1400 microns sieve.

Example 7

CBD Extract 10%

CBD extract with a 10% content of CBD provided by Medical Hemp (batchnumber MH131B Gold), was preheated to around 60° C. for around 0.5 to 1hour until the extract was in liquid form. The extract had a content offatty acids, glycerol, waxes, terpenes and flavonoids. After thepreheating process, the extract was applied as a thin layer on top ofone or more sugar alcohol particles, here isomalt. After mixing untilCBD was homogeneously distributed in the isomalt, the mixture was sievedthrough a 1400 microns sieve.

Example 8

CBD Isolate

CBD isolate from cannabis plant tissues (phytocannabinoid) with a 98.5%content of CBD provided by Medical Hemp (batch number MH18212) wasdissolved in an 96% ethanol solution. The ratio between the CBD isolateand ethanol was 1:1. Once CBD was dissolved in the ethanol, the CBDisolate was applied in a premix with one or more sugar alcoholparticles, here isomalt. After mixing until CBD was homogeneouslydistributed in the isomalt, the mixture was sieved through a 1400microns sieve.

Example 9

Preparation of Cannabinoid Sugar Alcohol Premix

A premix was made with CBD and sugar alcohol particles, here isomalt.The premix was made in a weight ratio of about 1:20 of CBD and isomaltwith either one of the forms of CBD outlined in Examples 6-8. CBD wasadded to the sugar alcohol particles and the powder was blended.

Example 10

Preparation of Cannabinoid Cyclodextrin Premix

CBD (extract or isolate) was added and dissolved in a 5% solution ofpolysorbate 80 to obtain a 10% solution of CBD. The 10% CBD solution wasslowly added and mixed into a solution with 10% cyclodextrin to form aCBD-cyclodextrin complex. The water was removed, whereupon the complexwas applied in a premix with water-soluble chewing gum ingredients, hereisomalt. After mixing until CBD was homogeneously distributed in theisomalt, the mixture was sieved through a 1400 microns sieve.

Example 11

Preparation of Cannabinoid Microcrystalline Cellulose Premix

A cannabinoid-microcrystalline cellulose (MCC) premix was made by firstadding free cannabinoid to poloxamer F68 (PF) to obtain a 10% blend ofcannabinoid in poloxamer F68. Butylated hydroxytoluene (BHT) was added(0.5%) to 50 grams of the cannabinoid-poloxamer F68 solid mix and addedto 50 grams of microcrystalline cellulose provided as Avicel PH 102 fromFMC Biopolymer. This was then mixed in a Kitchenaid mixer operated atabout 30 RPM for about 30 minutes at room temperature. This mixture wasequilibrated for about 30 minutes in a sealed container. Hereby, at 5%cannabinoid-MCC premix was obtained.

Example 12

A: Preparation of Tableted Chewing Gum with One Gum Layer

A first population of particles comprising water-insoluble gum baseprepared according to Example 1 and formulated according to Examples 2-5(GB) was mixed with a second population of particles comprisingwater-soluble chewing gum ingredients. Optionally, further population ofparticles were added as well as further optional ingredients.

The mixture was blended in a mixing container at 7-12 rpm and optionallyloaded with processing aid in order to improve free-flowing propertiesof the particles. The mixture was subsequently led to a standard tabletpressing machine (3090i, available from Fette GmbH) comprising dosingapparatus (P 3200 C, available from Fette GmbH, Germany) and pressedinto tableted chewing gum compositions. The filling depth in theapparatus was 7.5 mm and the diameter 15.0 mm. The tablets were pressedusing a pressing pressure of 33.0-33.6 kN and optionally prepressed witha pressing pressure of 1-7 kN. There were 75 punches on the rotor, andthe rotor speed used was 11 rpm. The individual tablets had a weight ofapprox. 1.35 g.

B: Preparation of Tableted Chewing Gum with One Gum Layer

A first population of particles comprising water-insoluble gum base inan amount of 36% by weight of particles was prepared according toExample 1 and formulated according to Examples 2-5 (GB). In thisExample, about 56% of isomalt was included in the first population ofparticles (unless stated otherwise), i.e. gum base and isomalt wasincluded in the same individual particles. Optionally, furtherpopulation of particles were added as well as further optionalingredients.

The mixture was blended in a mixing container at 7-12 rpm and optionallyloaded with processing aid in order to improve free-flowing propertiesof the particles. The mixture was subsequently led to a standard tabletpressing machine (3090i, available from Fette GmbH) comprising dosingapparatus (P 3200 C, available from Fette GmbH, Germany) and pressedinto tableted chewing gum compositions. The filling depth in theapparatus was 7.5 mm and the diameter 15.0 mm. The tablets were pressedusing a pressing pressure of 33.0-33.6 kN and optionally prepressed witha pressing pressure of 1-7 kN. There were 75 punches on the rotor, andthe rotor speed used was 11 rpm. The individual tablets had a weight ofapprox. 1.35 g.

Example 13

A: Preparation of Tableted Chewing Gum with One Layer Free of Gum Base

A population of particles comprising water-soluble chewing gumingredients was provided. Optionally, further population of particleswere added as well as further optional ingredients. However, gum baseparticles were not applied.

Before pressing, the mixture was blended in a mixing container at 7-12rpm and optionally loaded with processing aid in order to improvefree-flowing properties of the particles. The mixture was subsequentlyled to a standard tablet pressing machine (3090i, available from FetteGmbH) comprising dosing apparatus (P 3200 C, available from Fette GmbH,Germany) and pressed into a layer of the tableted chewing gumcompositions. The filling depth in the apparatus was 7.5 mm and thediameter 15.0 mm. The layer of the tablet was pressed using a pressingpressure of 33.0-33.6 kN. There were 75 punches on the rotor, and therotor speed used was 11 rpm.

Subsequently, a layer according to Example 12A was tableted on top ofthe prepared layer (does not apply for B-F below). The weight ratio ofthe two layers was 55 to 45 (gum base free layer to gum base layer). Theindividual tablets had a weight of approx. 1.6 g.

B: Preparation of Tableted Chewing Gum with One Layer Free of Gum Base

One layer was prepared according to Example 13A. Subsequently, anotherlayer according to Example 12B was tableted on top of the preparedlayer. The weight ratio of the two layers was 50 to 50 (Gum base freelayer to gum base layer). The individual tablets had a weight of approx.1.6 g.

C: Preparation of Tableted Chewing Gum with Two Gum Base Layers

One layer was prepared according to Example 12A. Subsequently, anotherlayer according to Example 12A was tableted on top of the preparedlayer. The weight ratio of the two layers was 50 to 50 (Gum base layerto gum base layer). The individual tablets had a weight of approx. 1.6g.

D: Preparation of Tableted Chewing Gum with Three Layers

One layer was prepared according to Example 13A. Subsequently, anotherlayer according to Example 12A was tableted on top of the preparedlayer. Subsequently, a further layer according to Example 13A wastableted on top of the layer from Example 12A. The weight ratio of thethree layers was 35 to 30 to 35 (gum base free layer to gum base layerto gum base free layer). The individual tablets had a weight of approx.1.6 g.

E: Preparation of Tableted Chewing Gum with Two Layers and a Gel CapsuleModule

One layer was prepared according to Example 13A. Subsequently, a moduleof non-particulate material was located centrally on top of the preparedlayer. In this example the non-particulate material was a gel capsule.Subsequently, another layer according to Example 12A was tableted on topof and fully enclosing the non-particulate material. The weight ratiowas 45 to 10 to 45 (gum base free layer to non-particulate material togum base layer). The individual tablets had a weight of approx. 1.6 g.

F: Preparation of Tableted Chewing Gum with Two Layers and Gum Module

One layer was prepared according to Example 13A. Subsequently, a moduleof non-particulate material was located on top of the prepared layer. Inthis example the non-particulate material was a sheet of conventionalextruded chewing gum. Subsequently, another layer according to Example12A was tableted on top of the sheet of extruded gum, the sheet beingvisible as a layer from a side view of the tablet. The weight ratio was45 to 10 to 45 (Gum base free layer to non-particulate material to gumbase layer). The individual tablets had a weight of approx. 1.6 g.

Example 14

Composition of Tableted Cannabinoid Chewing Gum

Cannabinoid chewing gum based on the procedure in Example 12A was madewith the formulations outlined in the examples below. The tabletedchewing gum had a weight of about 1.35 g for each piece and a content ofCBD of 10 mg for each piece. In all of the chewing gum examples, theamount of the various ingredients is given as % by weight of the chewinggum.

TABLE 1E CG Number CG100 CG101 CG102 CG103 CG104 GB10 36 — — — — GB11 —36 — — — GB12 — — 36 — — GB13 — — — 36 — GB14 — — — — 36 Isomalt 56.456.4 56.4 56.4 56.4 Menthol powder 2 2 2 2 2 Eucalyptus Powder 2 2 2 2 2Acesulfame K 0.05 0.05 0.05 0.05 0.05 Sucralose 0.05 0.05 0.05 0.05 0.05Processing aid 2.1 2.1 2.1 2.1 2.1 CBD 52%* 1.4 1.4 1.4 1.4 1.4 Total100 100 100 100 100 It was secured that CBD was thoroughly mixed intothe premixture as outlined in Example 9. CBD 52%* was prepared accordingto Example 6.

Example 15

Composition of Tableted Cannabinoid Chewing Gum

Cannabinoid chewing gum based on the procedure in Example 12A was madewith the formulations outlined in the examples below. The tabletedchewing gum had a weight of about 1.35 g for each piece and a content ofCBD of 10 mg for each piece. In all of the chewing gum examples, theamount of the various ingredients is given as % by weight of the chewinggum.

TABLE 1F CG Number CG105 CG106 CG107 CG108 CG109 GB15 36 — — — — GB16 —36 — — — GB17 — — 36 — — GB18 — — — 36 — GB19 — — — — 36 Isomalt 56.456.4 56.4 56.4 56.4 Menthol powder 2 2 2 2 2 Eucalyptus Powder 2 2 2 2 2Acesulfame K 0.05 0.05 0.05 0.05 0.05 Sucralose 0.05 0.05 0.05 0.05 0.05Processing aid 2.1 2.1 2.1 2.1 2.1 CBD 52%* 1.4 1.4 1.4 1.4 1.4 Total100 100 100 100 100 It was secured that CBD was thoroughly mixed intothe premixture as outlined in Example 9. CBD 52%* was prepared accordingto Example 6.

Example 16

Composition of Tableted Cannabinoid Chewing Gum

Cannabinoid chewing gum based on the procedure in Example 12A was madewith the formulations outlined in the examples below. The tabletedchewing gum had a weight of about 1.35 g for each piece and a content ofCBD of 10 mg for each piece. In all of the chewing gum examples, theamount of the various ingredients is given as % by weight of the chewinggum.

TABLE 1G CG Number CG110 CG111 CG112 CG113 CG114 GB20 36 — — — — GB21 —36 — — — GB22 — — 36 — — GB23 — — — 36 — GB24 — — — — 36 Isomalt 56.456.4 56.4 56.4 56.4 Menthol powder 2 2 2 2 2 Eucalyptus Powder 2 2 2 2 2Acesulfame K 0.05 0.05 0.05 0.05 0.05 Sucralose 0.05 0.05 0.05 0.05 0.05Processing aid 2.1 2.1 2.1 2.1 2.1 CBD 52%* 1.4 1.4 1.4 1.4 1.4 Total100 100 100 100 100 It was secured that CBD was thoroughly mixed intothe premixture as outlined in Example 9. CBD 52%* was prepared accordingto Example 6.

Example 17

Composition of Tableted Cannabinoid Chewing Gum

Cannabinoid chewing gum based on the procedure in Example 12A was madewith the formulations outlined in the examples below. The tabletedchewing gum had a weight of about 1.35 g for each piece and a content ofCBD of 10 mg for each piece. In all of the chewing gum examples, theamount of the various ingredients is given as % by weight of the chewinggum.

TABLE 1H CG Number CG115 CG116 CG117 CG118 CG119 GB25 36 — — — — GB26 —36 — — — GB27 — — 36 — — GB28 — — — 36 — GB29 — — — — 36 Isomalt 56.456.4 56.4 56.4 56.4 Menthol powder 2 2 2 2 2 Eucalyptus Powder 2 2 2 2 2Acesulfame K 0.05 0.05 0.05 0.05 0.05 Sucralose 0.05 0.05 0.05 0.05 0.05Processing aid 2.1 2.1 2.1 2.1 2.1 CBD 52%* 1.4 1.4 1.4 1.4 1.4 Total100 100 100 100 100 It was secured that CBD was thoroughly mixed intothe premixture as outlined in Example 9. CBD 52%* was prepared accordingto Example 6.

Example 18

Composition of Tableted Cannabinoid Chewing Gum

Cannabinoid chewing gum based on the procedure in Example 12A(CG120-121) and 12B (CG122-123) was made with the formulations outlinedin the examples below. One reference example was made with extrudedchewing gum made by rolling and scoring according to conventionalprinciples (CG124). The chewing gum had a weight of about 1.35 g foreach piece and a content of CBD of 10 mg for each piece. In all of thechewing gum examples, the amount of the various ingredients is given as% by weight of the chewing gum.

TABLE 1I CG Number CG120 CG121 CG122 CG123 CG124* GB10 36 36 36 36 36Isomalt 40.6 56.4 40.6 56.4 56.4 Talc 15.8 — 15.8 — — Menthol powder 2 22 2 2 Eucalyptus Powder 2 2 2 2 2 Acesulfame K 0.05 0.05 0.05 0.05 0.05Sucralose 0.05 0.05 0.05 0.05 0.05 Processing aid 2.1 2.1 2.1 2.1 2.1CBD 52%* 1.4 1.4 1.4 1.4 1.4 Total 100 100 100 100 100 It was securedthat CBD was thoroughly mixed into the premixture as outlined in Example9. CBD 52%* was prepared according to Example 6. CG124 is a referenceexample made by rolling and scoring (conventional extruded chewing gum).

Example 19

Composition of Tableted Cannabinoid Chewing Gum

Cannabinoid chewing gum based on the procedure in Example 12A was madewith the formulations outlined in the examples below. The tabletedchewing gum had a weight of about 1.35 g for each piece and a content ofCBD of 10 mg for each piece. In all of the chewing gum examples, theamount of the various ingredients is given as % by weight of the chewinggum.

TABLE 1J CG Number CG125 CG126 CG127 CG128 CG129 GB10 62.4 52.4 42.432.4 22.4 Isomalt 30 40 50 60 70 Menthol powder 2 2 2 2 2 EucalyptusPowder 2 2 2 2 2 Acesulfame K 0.05 0.05 0.05 0.05 0.05 Sucralose 0.050.05 0.05 0.05 0.05 Processing aid 2.1 2.1 2.1 2.1 2.1 CBD 52%* 1.4 1.41.4 1.4 1.4 Total 100 100 100 100 100 It was secured that CBD wasthoroughly mixed into the premixture as outlined in Example 9. CBD 52%*was prepared according to Example 6.

Example 20

Composition of Tableted Cannabinoid Chewing Gum

Cannabinoid chewing gum based on the procedure in Example 13A(CG130-133) and 13B (CG134) were made with the formulations outlined inthe examples below. The tableted chewing gum had a weight of about 1.6 gfor each piece and a content of CBD of 10 mg for each piece. The weightratio of the two layers was 55 to 45 (gum base free layer to gum baselayer) for CG130-133 and 50 to 50 for CG134. In all of the chewing gumexamples, the amount of the various ingredients is given as % by weightof the layer of the tableted chewing gum.

TABLE 1K CG Number CG130 CG131 CG132 CG133 CG134 Layer 1 GB10 36 60 6080 36 Isomalt 58.9 34.9 32.2 14.9 58.9 Menthol powder 2 2 2 2 2Eucalyptus Powder 2 2 2 2 2 Acesulfame K 0.05 0.05 0.05 0.05 0.05Sucralose 0.05 0.05 0.05 0.05 0.05 Processing aid 1 1 1 1 1 CBD 52%* — —2.7 — — Total 100 100 100 100 100 It was secured that CBD was thoroughlymixed into the premixture as outlined in Example 9. CBD 52%* wasprepared according to Example 6.

TABLE 1L CG Number CG130 CG131 CG132 CG133 CG134 Layer 2 GB10 — — — — —Isomalt 94.2 94.2 96.4 94.2 94.0 Menthol powder 2.5 2.5 2.5 2.5 2.5Eucalyptus Powder — — — — — Acesulfame K 0.05 0.05 0.05 0.05 0.05Sucralose 0.05 0.05 0.05 0.05 0.05 Processing aid 1 1 1 1 1 CBD 52%* 2.22.2 — 2.2 2.4 Total 100 100 100 100 100 It was secured that CBD wasthoroughly mixed into the premixture as outlined in Example 9. CBD 52%*was prepared according to Example 6.

Example 21

Composition of Tableted Cannabinoid Chewing Gum

Cannabinoid chewing gum based on the procedure in Example 13C(CG135-137) and 13D (CG138-139) were made with the formulations outlinedin the examples below. The tableted chewing gum had a weight of about1.6 g for each piece and a content of CBD of 10 mg for each piece. Theweight ratio of the two layers was 50 to 50 for CG135-137 and 35 to 30to 35 for CG138-139. In all of the chewing gum examples, the amount ofthe various ingredients is given as % by weight of the layer of thetableted chewing gum.

TABLE 1M CG Number CG135 CG136 CG137 CG138 CG139 Layer 1 GB10 36 60 6036 60 Isomalt 58.9 34.9 32.5 58.9 34.9 Menthol powder 2 2 2 2 2Eucalyptus Powder 2 2 2 2 2 Acesulfame K 0.05 0.05 0.05 0.05 0.05Sucralose 0.05 0.05 0.05 0.05 0.05 Processing aid 1 1 1 1 1 CBD 52%* — —2.4 — — Total 100 100 100 100 100 It was secured that CBD was thoroughlymixed into the premixture as outlined in Example 9. CBD 52%* wasprepared according to Example 6.

TABLE 1N CG Number CG135 CG136 CG137 CG138* CG139* Layer 2 (and 3*) GB1036 36 36 — — Isomalt 56.5 56.5 58.9 94.7 94.7 Menthol powder 2 2 2 2.52.5 Eucalyptus Powder 2 2 2 — — Acesulfame K 0.05 0.05 0.05 0.05 0.05Sucralose 0.05 0.05 0.05 0.05 0.05 Processing aid 1 1 1 1 1 CBD 52%* 2.42.4 — 1.7 1.7 Total 100 100 100 100 100 It was secured that CBD wasthoroughly mixed into the premixture as outlined in Example 9. CBD 52%*was prepared according to Example 6. It is noted that CG 138* and CG139* were made with 3 layers, where layer 1 was the middle layer andlayer 2 and 3 were located on opposite sides of layer 1. CG 135-137 weremade with two gum layers.

Example 22

Composition of Tableted Cannabinoid Chewing Gum

Cannabinoid chewing gum based on the procedure in Example 12A was madewith the formulations outlined in the examples below. The tabletedchewing gum had a weight of about 1.35 g for each piece and a content ofCBD of 10 mg for each piece. In all of the chewing gum examples, theamount of the various ingredients is given as % by weight of the chewinggum.

TABLE 1O CG Number CG140 CG141 CG142 CG143 CG144 GB10 36 36 36 36 36Isomalt 56.4 43.0 50.4 54.8 55.4 Menthol powder 2 2 2 2 2 EucalyptusPowder 2 2 2 2 2 Acesulfame K 0.05 0.05 0.05 0.05 0.05 Sucralose 0.050.05 0.05 0.05 0.05 Anti-sticking agent 2.1 2.1 2.1 2.1 2.1 CBD 52%* 1.4— — — 1.4 CBD-MCC 5%* — 14.8 — — CBD-MCC 10%* — — 7.4 — — CBD-cyclodex*— — — 3.0 — Self-emulsifying* — — — — 1 Total 100 100 100 100 100 It wassecured that CBD was thoroughly mixed into the premixture as outlined inExample 9. CBD 52%* was prepared according to Example 6. CBD-MCC 5%* wasprepared according to Example 11. CBD-MCC 10%* was prepared according toExample 11 with a higher amount of CBD. CBD-cyclodex* isCBD-cyclodextrin complex prepared according to Example 10 and 25%loaded. Self-emulsifying* was prepared with a self-emulsifier, herepolysorbate.

Example 23

Coating of Tableted Chewing Gum

A hard coating was prepared for selected samples with the followingcomposition:

TABLE 1P Hard coating Ingredients % by weight Number CG145 CG146Maltitol 56.9 56.9 Water 22.7 24.8 Mannitol 11 11 gummi arabicum 4 4Titandioxid 1 1 Polysorbate 0.1 0.1 CBD 52%* 4.3 — CBD isolate* — 2.2Total 100 100 It was secured that CBD was thoroughly mixed into thepremixture as outlined in Example 9. CBD 52%* was prepared according toExample 6. CBD isolate* was prepared according to Example 8. The coatingwas provided to samples of CG100 from Example 15.

The coating was applied as a pre-heated suspension as outlined above to1.35 g tableted chewing gum with the formulation of CG100 in Example 15,except that CBD 52% or CBD isolate was substituted with isomalt inCG100. Hence, CBD was not present in the tableted chewing gum, but onlyin the coating. A total of 10 mg CBD was present in the coated tablet.The suspension was applied in 3 subsequent steps according toconventional coating techniques to a total of 0.45 g coating to the 1.35g tableted chewing gum. This corresponds to a ratio of tableted chewinggum to coating on 75:25.

Example 24

In Vivo Testing of Release

A sample was chewed with a chewing frequency of 60 chews pr. minute for3 or 5 minutes in a test panel of 8 test persons. The test person was ahealthy person appointed on an objective basis according to specifiedrequirements. After 3 or 5 minutes, the content of CBD was measured inthe remaining chewing gum residue. The chewing gum was subject to triplemeasurements for each of the 8 test persons, giving a total of 24measurements for each sample. An average of the 24 measurements wascalculated and the weight % release was calculated based on the originalcontent of CBD in the sample. The content of CBD was measured in theremaining chewing gum residue. The chewing gum residue was positioned ina flask and weighted. Subsequently, an organic solvent was added fordissolution purposes, and the mixture was mixed on a laboratory shakerovernight. The organic phase was diluted and centrifuged. Thesupernatant was injected directly to an HPLC system and analyzed by anassay method.

Example 25

In Vitro Testing of Release

In vitro release of CBD was established by means of a chewing machine(Dissolution Test for Chewing Gums, General Monograph 2.9.25. InEuropean Pharmacopoeia, 5th ed). A chewing chamber was filled with 20 mlbuffer (phosphate buffer pH 7.4). The chewing gum sample was placed inthe chamber and the chewing machine was initiated at 20 degrees Celsiuswith 1 chew per second. After 3 or 5 minutes of chewing, the machine wasstopped and the chewing gum sample (residue) was placed in a vial. Ifmore release time points are needed (release profile), the chewingbuffer must be exchanged with 20 ml of fresh buffer every five minutes.The content of CBD was measured in the remaining chewing gum residue.The chewing gum residue was positioned in a flask and weighted.Subsequently, an organic solvent was added for dissolution purposes, andthe mixture was mixed on a laboratory shaker overnight. The organicphase was diluted and centrifuged. The supernatant was injected directlyinto an HPLC system and analyzed by an assay method.

Example 26

Stability Testing Method

For stability testing, the ICH guideline is used; 25° C./60% RH (2years), 30° C./65% RH (1 year), 40° C./75% RH (3 months). All sampleswere packed in duma bottles before stored in the conditions. All sampleswere sensorially and analytically evaluated. The content of CBD wasmeasured in the remaining chewing gum residue. The chewing gum residuewas positioned in a flask and weighted. Subsequently, an organic solventwas added for dissolution purposes, and the mixture was mixed on alaboratory shaker overnight. The organic phase was diluted andcentrifuged. The supernatant was injected directly into an HPLC set-upand analyzed by an assay method. The following method was able toseparate and quantify CBD, delta-9 THC, delta-8 THC and CBN.

Example 27

CBD Delivered to the Oral Mucosa

A sample was chewed in vivo with a chewing frequency of 60 chews pr.minute for 5 minutes in a test panel of 8 test persons. The test personwas not allowed to swallow during the procedure. After one minute,saliva was obtained from the test person and collected in a vessel forlater analysis. In tests for 5 minutes release, the same procedure wasfollowed until 5 minutes where the last sample was collected and addedto the same vessel for aggregated analysis. The test person was ahealthy person appointed on an objective basis according to specifiedrequirements. the aggregated saliva sample was collected after 5minutes, the content of CBD was measured in the saliva. The content ofCBD was also measured in the remaining chewing gum residue. The chewinggum residue was positioned in a flask and weighted. Subsequently, anorganic solvent was added for dissolution purposes, and the mixture wasmixed on a laboratory shaker overnight. The organic phase was dilutedand centrifuged. The supernatant was injected directly into an HPLCsystem and analyzed by an assay method. The gum and saliva was subjectto 3 triple measurements for each of the 8 test persons, giving a totalof 24 measurement for each sample. An average of the 24 measurements wascalculated and the weight % release was calculated. By comparing theamount of CBD in the remaining chewing gum residue and the amount of CBDin the saliva, the amount of CBD delivered to the oral mucosa could beestimated.

Example 28

Sensorics Evaluation Test Set-Up

Apart from release measurements, either in vivo or in vitro, as well asstability tests of the tableted chewing gum, sensorics tests were alsoperformed to reveal very important characteristics and properties of thetableted chewing gum. These sensorics parameters are important asindicators of the structure of the chewing gum composition and thebehavior of the gum when chewed. The structure is the underlyingguidance as to how the chewing gum resembles the structure of acomparative chewing gum, which is set as the standard in the testseries, i.e. the chewing gums are compared to each other in the testseries of preferably 5 samples. The test set-up was composed of 8 testpersons in a test panel. Each of the test persons were healthyindividuals appointed on an objective basis according to specifiedrequirements. The sensory analysis was performed according to ISO4121-2003 in testing conditions following ISO 8589. The result is anaverage of the results of the 8 individuals.

The test persons gave a rating from “+” to “+++++”, where “+” is poorand “+++++” is excellent and comparable to the standard, i.e. “+++++”means that the gum was comparable to the standard and “+” means that thegum was very far from comparable to the standard. “0” indicated that itwas not tested.

Five different parameters were tested in a test panel:

Initial chew Texture Flavor Sweetness Off-notes

“Initial chew”—the first impression of the gum when chewed within thefirst 30 seconds. For instance, a very hard and viscous structure gave avery low rating and a very brittle structure also gave a very lowrating.

“Texture”—the overall impression of the gum after 30 seconds of chewinggum or when the gum has gained the structure of a steady state. Forinstance, a very hard structure gave a very low rating and a very smoothstructure also gave a very low rating.

“Flavor”—the overall impression of the gum during chewing with respectto flavor. For instance, a very low flavor experience gave a very lowrating and a too high flavor experience that was not comparable to thestandard also gave a very low rating.

“Sweetness”—the overall impression of the taste of the gum duringchewing with respect to sweetness. For instance, if the sweetness wasdecreasing rapidly a very low rating was given and if the sweetness wastoo high giving an uncomfortable feeling a very low rating was alsogiven.

“Off-notes”—the overall impression of the off-note from the one or morecannabinoids in the composition during chewing. For instance, ifoff-notes (grass, bitter notes, irritation in the throat) wereexperienced in the throat, a low rating was given and if otheruncomfortable sensations was experienced a low rating was also given.

Example 29

Sensorics Evaluation of Cannabinoid Chewing Gum

TABLE 2A Evaluation of Examples 14-22 according to Example 28. CGInitial chew Texture Flavor Sweetness Off-notes CG 100 +++++ +++++ ++++++++ ++++ CG 101 +++++ +++++ ++++ ++++ ++++ CG 102 +++++ +++++ ++++ ++++++++ CG 103 ++++ +++ +++ +++ ++++ CG 104 ++++ ++++ ++++ ++++ ++++ CG 105+++++ +++++ ++++ ++++ ++++ CG 106 +++++ +++++ ++++ ++++ ++++ CG 107+++++ +++++ ++++ ++++ ++++ CG 108 ++++ +++ +++ +++ +++ CG 109 +++ ++++++++ +++ +++ CG 110 0 0 +++++ ++++ +++++ CG 111 0 0 ++++ +++++ +++++ CG112 0 0 +++++ +++++ +++++ CG 113 0 0 ++++ ++++ ++++ CG 114 0 0 +++++++++ +++++ CG 115 +++++ +++++ ++++ ++++ ++++ CG 116 +++++ +++++ ++++++++ ++++ CG 117 ++ + ++ + ++++ CG 118 + + ++ + ++++ CG 119 ++ ++ ++++++ ++++ CG 120 ++++ ++++ +++ +++ +++ CG 121 +++++ +++++ ++++ ++++ ++++CG 122 ++++ ++++ +++ +++ +++ CG 123 +++++ ++++ ++++ ++++ ++++ CG 124 ++++ +++ ++ ++ CG 125 +++ +++ ++++ +++ +++ CG 126 ++++ ++++ ++++ ++++ +++CG 127 +++++ +++++ +++++ +++++ ++++ CG 128 +++++ +++++ +++++ +++++ ++++CG 129 ++++ ++++ ++++ +++ +++ CG 130 +++++ +++++ +++++ ++++ ++++ CG 131+++++ +++++ ++++ ++++ +++ CG 132 ++++ ++++ ++++ +++++ ++++ CG 133 ++++++++ ++++ ++++ ++++ CG 134 +++++ +++++ ++++ ++++ ++++ CG 135 ++++ ++++++++ ++++ ++++ CG 136 +++++ +++++ ++++ ++++ ++++ CG 137 ++++ ++++ +++++++ ++++ CG 138 +++++ +++++ +++ +++ ++++ CG 139 +++++ +++++ ++++ ++++++++++ CG 140 +++++ +++++ ++++ ++++ ++++ CG 141 +++++ +++++ ++++ ++++++++ CG 142 ++++ ++++ ++++ ++++ ++++ CG 143 +++++ +++++ +++++ ++++ +++CG 144 +++++ +++++ +++++ ++++ +++

Example 30

Release of Cannabinoid

TABLE 2B Chewing gum samples from Example 14 was tested for releaseafter 3 or 5 minutes of in vitro chewing according to the test method ofExample 25. The value indicates weight % of cannabinoid released fromthe chewing gum sample (CG). CG Number CG100 CG101 CG102 CG103 CG104 3minutes 39 37 40 34 30 5 minutes 43 42 44 38 36

The result shows that in the outer end of the ranges according to theinvention, the release was lower, but still acceptable (CG103 andCG104). However, the ranges should be seen combined, such that the rangeof each of elastomer plasticizers and natural resin contributes incombination to the overall effect and release properties of the chewinggum. Hence, if an amount in the end of the range for natural resin isapplied, the amount of elastomer plasticizer may to some extendcounteract the negative effect.

Example 31

Release of Cannabinoid

TABLE 2C Chewing gum samples from Example 15 was tested for releaseafter 3 or 5 minutes of in vitro chewing according to the test method ofExample 25. The value indicates weight % of cannabinoid released fromthe chewing gum sample (CG). CG Number CG105 CG106 CG107 CG108 CG109 3minutes 38 39 43 33 31 5 minutes 43 44 45 37 35

The result shows that in the outer end of the ranges according to theinvention, the release was lower, but still acceptable (CG108 andCG109). However, the ranges should be seen combined, such that the rangeof each of elastomer plasticizers and natural resin contributes incombination to the overall effect and release properties of the chewinggum. Hence, if an amount in the end of the range for natural resin isapplied, the amount of elastomer plasticizer may to some extendcounteract the negative effect.

The release of CG 110-114 was comparable to CG105-109.

Example 32

Release of Cannabinoid

TABLE 2D Chewing gum samples from Example 17 was tested for releaseafter 3 or 5 minutes of in vitro chewing according to the test method ofExample 25. The value indicates weight % of cannabinoid released fromthe chewing gum sample (CG). CG Number CG115 CG116 CG117 CG118 CG119 3minutes 39 37 9 8 16 5 minutes 43 42 17 16 19

The result is clear in the sense that addition of VA-VL to thecomposition provides a much lower release (CG 117-119) than by the useof the polymers and natural resin according to the present invention. Inaddition, the sensorics properties by the use of VA-VL (see above) alsomakes it clear that VA-VL is not preferred.

Example 33

Release of Cannabinoid

TABLE 2E Chewing gum samples from Example 18 was tested for releaseafter 3 or 5 minutes of in vitro chewing according to the test method ofExample 25. The value indicates weight % of cannabinoid released fromthe chewing gum sample (CG). CG Number CG120 CG121 CG122 CG123 CG124 3minutes 31 39 30 38 10 5 minutes 34 43 35 41 14

The addition of talc to the composition was expected to give a higherrelease of CBD since it was expected that talc would provide a moreporous structure to the tableted chewing gum and thereby promote betterrelease of CBD. However, this was not seen (CG120 and CG122) and itappears that the amount of sugar alcohols is more important for releasecharacteristics than previously expected. With respect to the extrudedgum reference example (CG124), it is seen that the release propertieswere significantly lower than the examples according to the invention.

Example 34

Release of Cannabinoid

TABLE 2F Chewing gum samples from Example 19 was tested for releaseafter 3 or 5 minutes of in vitro chewing according to the test method ofExample 25. The value indicates weight % of cannabinoid released fromthe chewing gum sample (CG). CG Number CG125 CG126 CG127 CG128 CG129 3minutes 30 35 39 40 44 5 minutes 34 41 43 46 56

The results shows that a low amount of sugar alcohol in the gum (CG125)has an effect on the release of cannabinoids and that a higher amountwas desirable. However, a too high amount of sugar alcohol (CG129)affected other properties of the chewing gum as seen in the sensoricsresults which was not expected. It is noted that the release propertiesshould be seen in combination with the sensorics properties.

Example 35

Release of Cannabinoid

TABLE 2G Chewing gum samples from Example 20 was tested for releaseafter 3 or 5 minutes of in vitro chewing according to the test method ofExample 25. The value indicates weight % of cannabinoid released fromthe chewing gum sample (CG). CG Number CG130 CG131 CG132 CG133 CG134 3minutes 65 60 48 54 66 5 minutes 68 63 54 58 70

The result shows that the best release rate was obtained with aformulation of CG130 and CG134. In these examples, the gum base contentwas lower than in CG131 and CG133. When CBD was located in the gumlayer, the release was somewhat lower (CG132).

Example 36

Release of Cannabinoid

TABLE 2H Chewing gum samples from Example 21 was tested for releaseafter 3 or 5 minutes of in vitro chewing according to the test method ofExample 25. The value indicates weight % of cannabinoid released fromthe chewing gum sample (CG). CG Number CG135 CG136 CG137 CG138 CG139 3minutes 37 34 32 71 65 5 minutes 41 38 33 75 71

Generally, a slightly lower release was obtained when the content of gumbase was increased, both in the two-layered tableted chewing gum and inthe three-layered tableted chewing gum.

Example 37

Release of Cannabinoid

TABLE 2I Chewing gum samples from Example 22 was tested for releaseafter 3 or 5 minutes of in vitro chewing according to the test method ofExample 25. The value indicates weight % of cannabinoid released fromthe chewing gum sample (CG). CG Number CG140 CG141 CG142 CG143 CG144 3minutes 39 17 19 46 49 5 minutes 43 21 25 52 58

The overall result shows that release promoting systems, such as acyclodextrin complex with CBD (CG143) or self-emulsifiers systems(CG144), may be a particular advantage according to the invention if ahigher release is desirable. However, the use of microcrystallinecellulose as a carrier in a 10% MCC-system (CG142) did provide a loweroverall release which was even lower for a 5% MCC-system (CG141).

Example 38

Coating with CBD

TABLE 3A Chewing gum samples from Example 23 was tested for releaseafter 3 or 5 minutes of in vitro chewing according to the test method ofExample 25. The value indicates weight % of cannabinoid released fromthe chewing gum sample (CG). CG Number CG145 CG146 3 minutes 60 55 5minutes 59 61

The result was highly surprising since it was expected that a majoramount of CBD from the coating was absorbed in the chewing gum uponchewing. However, the result shows that application of one or morecannabinoids into a coating, such as a hard coating, may be a promisingway to deliver cannabinoids. Also, by combining the application of oneor more cannabinoids in the coating as well as in the tableted chewinggum, controlled release of cannabinoids may be obtained. This may alsobe used to provide a biphasic release of cannabinoids, such that aninitial high release is provided by the coating and a more sustainedrelease is provided by incorporating the cannabinoids in the tabletedchewing gum.

Example 39

CBD Delivered to the Oral Mucosa

Tests were conducted in accordance with the test method of Example 27.The tests were performed for CG100 and CG101. The values for the CBDcontent in saliva and in the chewing gum residue were measured after 5min of chewing. From these values, the content of CBD delivered to theoral mucosa could be calculated.

TABLE 3B Chewing gum samples from Example 14 were tested for content ofCBD delivered to the oral mucosa after 5 minutes of in vivo chewingaccording to the test method of Example 27. The values indicate weight %of cannabinoid based on the one or more cannabinoids present in theinitial formulation. CG Number CG100 CG101 CBD in saliva 11 9 CBD inresidue 57 58 CBD delivered to mucosa 32 33

The results of the tests were very surprising as a major part of the CBDreleased after 5 minutes of chewing was delivered to the oral mucosa. Itwas expected that a much higher amount of CBD was present in the salivaafter 5 minutes of chewing, but only a relatively low amount of CBD wasfound in the saliva. Hence, the chewing gum formulation of the inventionis very suitable for delivery of cannabinoids to the oral mucosa, muchbetter than would have been expected.

Example 40

CBD Delivered to the Oral Mucosa

Tests were conducted in accordance with the test method of Example 27.The tests were performed for CG130 and CG131. The values for the CBDcontent in saliva and in the chewing gum residue were measured after 5min of chewing. From these values, the content of CBD delivered to theoral mucosa could be calculated.

TABLE 3C Chewing gum samples from Example 20 were tested for content ofCBD delivered to the oral mucosa after 5 minutes of in vivo chewingaccording to the test method of Example 27. The values indicate weight %of cannabinoid based on the one or more cannabinoids present in theinitial formulation. CG Number CG130 CG131 CBD in saliva 23 22 CBD inresidue 32 34 CBD delivered to mucosa 45 44

The results of the tests were very surprising as a major part of the CBDreleased after 5 minutes of chewing was delivered to the oral mucosa. Itwas expected that a much higher amount of CBD was present in the salivaafter 5 minutes of chewing, but only a relatively low amount of CBD wasfound in the saliva. Hence, the chewing gum formulation of the inventionis very suitable for delivery of cannabinoids to the oral mucosa, muchbetter than would have been expected.

Example 41

CBD Delivered to the Oral Mucosa

Tests were conducted in accordance with the test method of Example 27.The tests were performed for CG135 and CG136. The values for the CBDcontent in saliva and in the chewing gum residue were measured after 5min of chewing. From these values, the content of CBD delivered to theoral mucosa could be calculated.

TABLE 3D Chewing gum samples from Example 21 were tested for content ofCBD delivered to the oral mucosa after 5 minutes of in vivo chewingaccording to the test method of Example 27. The values indicate weight %of cannabinoid based on the one or more cannabinoids present in theinitial formulation. CG Number CG135 CG136 CBD in saliva 8 7 CBD inresidue 59 62 CBD delivered to mucosa 33 31

The results of the tests were very surprising as a major part of the CBDreleased after 5 minutes of chewing was delivered to the oral mucosa. Itwas expected that a much higher amount of CBD was present in the salivaafter 5 minutes of chewing, but only a relatively low amount of CBD wasfound in the saliva. Hence, the chewing gum formulation of the inventionis very suitable for delivery of cannabinoids to the oral mucosa, muchbetter than would have been expected.

Example 42

CBD Delivered to the Oral Mucosa

Tests were conducted in accordance with the test method of Example 27.The tests were performed for CG145 and CG146. The values for the CBDcontent in saliva and in the chewing gum residue were measured after 5min of chewing. From these values, the content of CBD delivered to theoral mucosa could be calculated.

TABLE 3E Chewing gum samples from Example 23 were tested for content ofCBD delivered to the oral mucosa after 5 minutes of in vivo chewingaccording to the test method of Example 27. The values indicate weight %of cannabinoid based on the one or more cannabinoids present in theinitial formulation. CG Number CG145 CG146 CBD in saliva 28 31 CBD inresidue 41 39 CBD delivered to mucosa 31 30

The results of the tests were surprising as a very high amount of CBDreleased after 5 minutes of chewing was delivered to the oral mucosa. Itwas expected that a much higher amount of CBD was present in the salivaafter 5 minutes of chewing. It was not expected that such a high contentof CBD could be delivered to the oral mucosa with the present chewinggum formulation. In fact, the content of CBD would be higher ifpolysorbate was not applied in the coating suspension since polysorbatefacilitates emulsifying properties of the saliva which prevent CBD to bedelivered to the oral mucosa to an even higher degree.

By varying the content of CBD in the coating and the content of CBD inthe chewing gum, a controlled delivery system may be established.

The invention claimed is:
 1. A method of oral administration ofcannabinoids in a tableted chewing gum composition comprisingwater-soluble chewing gum ingredients and water-insoluble gum baselocated in a plurality of particles, and one or more cannabinoids, themethod comprising the steps of: i) premixing the one or morecannabinoids with one or more carriers to obtain a uniform premixture,the one or more carriers comprising one or more sugar alcohol carries orone or more sugar carriers, with the proviso that the one or morecarriers do not limit free transfer and release of the one or morecannabinoids in a chewing gum formulation; ii) blending the uniformpremixture with at least a part of the plurality of particles to obtaina flowable mixture for tableting; iii) pressing the flowable mixture fortableting in a direct compression apparatus by means of punches toobtain a tableted chewing gum composition with reduced bulk volume andformation of bonds between at least a part of the plurality ofparticles; and iv) subjecting the tableted chewing gum composition to aperson in need thereof, whereby the chewing gum composition generatessaliva and delivers more than 20% by weight and less than 60% by weightof the one or more cannabinoids to the oral mucosa during the first 5minutes of chewing, the delivery of the one or more cannabinoids beingestimated by measuring the content of the one or more cannabinoids insaliva collected during and after the 5 minutes of chewing and generatedat a chewing frequency of 60 chews each minute without swallowing salivaduring the 5 minutes of chewing and measuring the content of the one ormore cannabinoids in the remaining chewing gum residue.
 2. The methodaccording to claim 1, wherein the chewing gum composition delivers morethan 30% by weight of the one or more cannabinoids to the oral mucosaduring the first 5 minutes of chewing.
 3. The method according to claim1, wherein the plurality of particles includes a first population ofparticles comprising water-insoluble gum base and a second population ofparticles comprising water-soluble chewing gum ingredients.
 4. Themethod according to claim 3, wherein the first population of particlesis present in an amount of 20 to 60% by weight of the tableted chewinggum composition.
 5. The method according to claim 3, wherein the secondpopulation of particles is present in an amount of 40 to 80% by weightof the tableted chewing gum composition.
 6. The method according toclaim 3, wherein the content of water-insoluble gum base of the firstpopulation of particles is more than 30% by weight of the firstpopulation of particles.
 7. The method according to claim 3, wherein thecontent of water-soluble chewing gum ingredients of the secondpopulation of particles is more than 50% by weight of the secondpopulation of particles, the second population of particles being freeof water-insoluble gum base.
 8. The method according to claim 3, whereinthe one or more cannabinoids is present in the second population ofparticles comprising water-soluble chewing gum ingredients.
 9. Themethod according to claim 1, wherein the water-insoluble gum base ispartly located in a first layer of the chewing gum composition and thewater-soluble chewing gum ingredients are partly located in a secondlayer of the chewing gum composition together with the one or morecannabinoids.
 10. The method according to claim 1, wherein thewater-insoluble gum base is located in a first layer of the chewing gumcomposition and the water-soluble chewing gum ingredients are partlylocated in a second layer of the chewing gum composition together withthe one or more cannabinoids.
 11. The method according to claim 1,wherein the one or more cannabinoids is selected from the groupconsisting of cannabidiol (CBD), cannabidiolic acid (CBDA),cannabidivarin (CBDV), salts thereof, and derivatives thereof.
 12. Themethod according to claim 1, wherein the one or more cannabinoids isselected from the group consisting of tetrahydrocannabinol (THC),tetrahydrocannabinolic acid (THCA), tetrahydrocannabivarin (THCV), saltsthereof, and derivatives thereof.
 13. The method according to claim 1,wherein the one or more cannabinoids comprises at least onephytocannabinoid that forms part of an extract when formulated in thetableted chewing gum.
 14. The method according to claim 1, wherein thechewing gum further comprises terpenes.
 15. The method according toclaim 1, wherein the one or more cannabinoids comprises at least oneisolated cannabinoid.
 16. The method according to claim 1, wherein theone or more cannabinoids comprises at least one water-solublecannabinoid.
 17. The method according to claim 1, wherein the chewinggum comprises one or more emulsifiers.
 18. The method according to claim1, wherein the chewing gum comprises one or more solubilizers.
 19. Themethod according to claim 1, wherein the chewing gum comprises aself-emulsifying agent.
 20. The method according to claim 1, wherein thepremixture comprises a lipid carrier for the one or more cannabinoids.21. A method of alleviating or treating a medical condition comprisingadministering a method of oral administration according to claim
 1. 22.The method according to claim 1, wherein the water-soluble chewing gumingredients comprise one or more sugar alcohols in an amount of 35-80%by weight of the tableted chewing gum composition, or one or more sugarsin an amount of 35-80% by weight of the tableted chewing gumcomposition.
 23. The method according to claim 1, wherein thewater-soluble chewing gum ingredients comprise: one or more sugaralcohols selected from the group consisting of xylitol, sorbitol,mannitol, maltitol, isomaltitol, isomalt, erythritol, lactitol,maltodextrin, and combinations thereof, in an amount of 35-80% by weightof the tableted chewing gum composition, or one or more sugars selectedfrom the group consisting of dextrose, sucrose, maltose, fructose,lactose, and combinations thereof, in an amount of 35-80% by weight ofthe tableted chewing gum composition.
 24. A method of oraladministration of cannabinoids in a tableted chewing gum compositioncomprising water-soluble chewing gum ingredients and water-insoluble gumbase located in a plurality of particles, and one or more cannabinoids,the method comprising the step of: i) premixing the one or morecannabinoids with one or more carriers to obtain a uniform premixture,the one or more carriers comprising one or more sugar alcohol carriersor one or more sugar carriers, with the proviso that the one or morecarriers do not include polymer carriers; ii) blending the uniformpremixture with at least a part of the plurality of particles to obtaina flowable mixture for tableting; iii) pressing the flowable mixture fortableting in a direct compression apparatus by means of punches toobtain a compact coherent tablet without a brittle structure in theinitial chew; and iv) subjecting the tableted chewing gum composition toa person in need thereof, whereby the chewing gum composition generatessaliva and delivers more than 20% by weight of the one or morecannabinoids to the oral mucosa during the first 5 minutes of chewing,the delivery of the one or more cannabinoids being estimated bymeasuring the content of the one or more cannabinoids in salivacollected during and after the 5 minutes of chewing and generated at achewing frequency of 60 chews each minute without swallowing salivaduring the 5 minutes of chewing and measuring the content of the one ormore cannabinoids in the remaining chewing gum residue.
 25. A method oforal administration of cannabinoids in a tableted chewing gumcomposition comprising water-soluble chewing gum ingredients andwater-insoluble gum base located in a plurality of particles, and one ormore cannabinoids, the method comprising the steps of: i) premixing theone or more cannabinoids with one or more carriers to obtain a uniformpremixture, the one or more carriers comprising one or more sugaralcohol carriers, one or more sugar carriers or one or moremicrocrystalline cellulose species; ii) blending the uniform premixturewith at least a part of the plurality of particles to obtain a flowablemixture for tableting; iii) pressing the flowable mixture for tabletingin a direct compression apparatus by means of punches to obtain atableted chewing gum composition with reduced bulk volume and formationof bonds between at least a part of the plurality of particles; and iv)subjecting the tableted chewing gum composition to a person in needthereof, whereby the chewing gum composition generates saliva anddelivers more than 20% by weight of the one or more cannabinoids to theoral mucosa during the first 5 minutes of chewing, the delivery of theone or more cannabinoids being estimated by measuring the content of theone or more cannabinoids in saliva collected during and after the 5minutes of chewing and generated at a chewing frequency of 60 chews eachminute without swallowing saliva during the 5 minutes of chewing andmeasuring the content of the one or more cannabinoids in the remainingchewing gum residue.
 26. A method of oral administration of cannabinoidsin a tableted chewing gum composition comprising water-soluble chewinggum ingredients and water-insoluble gum base located in a plurality ofparticles, and one or more cannabinoids, the method comprising the stepsof: i) premixing the one or more cannabinoids with one or more carriersto obtain a uniform premixture, the one or more carriers comprising alipid carrier for the one or more cannabinoids; ii) blending the uniformpremixture with at least a part of the plurality of particles to obtaina flowable mixture for tableting; iii) pressing the flowable mixture fortableting in a direct compression apparatus by means of punches toobtain a tableted chewing gum composition with reduced bulk volumewithout a crumbling structure in the initial chew; and iv) subjectingthe tableted chewing gum composition to a person in need thereof,whereby the chewing gum composition generates saliva and delivers morethan 20% by weight and less than 60% by weight of the one or morecannabinoids to the oral mucosa during the first 5 minutes of chewing,the delivery of the one or more cannabinoids being estimated bymeasuring the content of the one or more cannabinoids in salivacollected during and after the 5 minutes of chewing and generated at achewing frequency of 60 chews each minute without swallowing salivaduring the 5 minutes of chewing and measuring the content of the one ormore cannabinoids in the remaining chewing gum residue.
 27. The methodaccording to claim 26, wherein the one or more cannabinoids are presentin an amount of 0.1 to 100 mg.
 28. The method according to claim 26,wherein the one or more cannabinoids are present in an amount of 0.1 to50 mg.
 29. The method according to claim 26, wherein the one or morecannabinoids are present in an amount of 0.1 to 30 mg.